Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases

Abstract

Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a general overview of bone’s main players (bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts) that participate in bone remodeling. Placing emphasis on the family of extracellular matrix metalloproteinases (MMPs), we describe how: (i) Convergence of multiple protease families (including MMPs and cysteine proteinases) ensures complexity and robustness of the bone remodeling process, (ii) Enzymatic activity of MMPs affects bone physiology at the molecular and cellular levels and (iii) Either overexpression or deficiency/insufficiency of individual MMPs impairs healthy bone remodeling and systemic metabolism. Today, it is generally accepted that proteolytic activity is required for the degradation of bone tissue in osteoarthritis and osteoporosis. However, it is increasingly evident that inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. We argue that there remains a need to rethink the role played by proteases in bone physiology and pathology.

Introduction

Bone is a hard, dense, rigid form of highly specialized connective tissue making up the skeleton of vertebrates. Bone protects internal organs, supports body structures, and aids in locomotion (Maffioli and Derosa, 2015). In addition, bone provides an environment for hematopoiesis (i.e., formation and development of blood cells) in the bone marrow, and acts as a homeostatic reservoir of calcium, phosphorus, insulin-like growth factors, transforming growth factor-β, and cytokines. Bone buffers the blood against drastic pH changes, thus detoxifying the circulation from heavy metals (Rauner et al., 2012). Bone develops by intramembranous ossification (e.g., bone of the clavicle, some skull bones), endochondral ossification (e.g., the appendicular and axial skeleton) or pseudo-metamorphic ossification (Rauner et al., 2012).

Bone remodeling is a complex process involving the sequential resorption of bone tissue and deposition of new bone at the same site (Kerschan-Schindl and Ebenbichler, 2012). Together with bone structure, geometry, size, and density, remodeling determines bone’s overall mechanical properties (e.g., the strength) (Mosekilde et al., 1993; Jiang et al., 1997; Ikeda et al., 2003; Shahnazari et al., 2009) as well as enables the repair of damaged bone and the adaption of bone to changing biomechanical forces (Kerschan-Schindl and Ebenbichler, 2012).

We review here the prevailing view of the bone remodeling process with an emphasis on well-accepted and newly emerging roles played by matrix metalloproteinases (MMPs) and cysteine proteinases in this process. Finally, we review the increasing number of instances in which inactivating mutations in MMP genes are found to lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth.

General Overview on the Cycle of Bone Remodeling

The bone remodeling process consists of four distinct consecutive phases spanning over 3–6 months (Datta et al., 2008).

The first phase of bone remodeling is known as the ‘activation phase’ and can be triggered by mechanical and nutritional stress on the bone as well as by hormones (e.g., parathyroid hormone, estrogen) (Parra-Torres et al., 2013). As described in Table 1, terminally differentiated osteocyte cell is a key player in the activation phase (Rauner et al., 2012; Parra-Torres et al., 2013).

The second phase lasts 8–10 days (Teitelbaum, 2007) and is called the ‘bone resorption phase’ – a process by which large multinucleated osteoclast cells break down old bone organic matrix impregnated with minerals (e.g., calcium phosphate nanocrystals), as described in Table 2.

The third ‘reversal’ phase connects osteoclastic bone tissue resorption and osteoblastic bone tissue formation (Delaisse, 2014) and lasts 7–14 days (Pettit et al., 2008; Hienz et al., 2015). After departure of the osteoclast from a cavity in bones undergoing resorption, which is a resorptive lacuna known as the Howship’s lacuna, bone lining cells occupy the Howship’s lacuna and clean it (Everts et al., 2002). The cleaning process occurs by enwrapping and digesting non-mineralized collagenous proteins protruding from the bone surface left by osteoclasts. This cleaning process is a requirement for the subsequent deposition of a first layer of collagen along the Howship’s lacuna (Everts et al., 2002). Four types of osteoclast-derived coupling factors stimulate bone formation during the reversal phase: (i) Matrix-derived factors including transforming growth factor-β, bone morphogenetic protein-2, platelet-derived growth factor, and insulin-like growth factors, which are released during bone tissue resorption, (ii) Osteoclast-secreted factors, including cardiotrophin-1, sphingosine-1-phosphate, collagen triple helix repeat containing 1, and complement factor 3a, (iii) Osteoclast membrane-bound factors such as EphrinB2 and Semaphorin D, and (iv) Structural changes brought about by the osteoclast on the bone tissue surface (Sims and Martin, 2014). Reversal cells originating from pre-osteoblast cells (Andersen et al., 2013) colonize the osteoclast-eroded surface and respond to osteoclast-derived messages and coupling factors along with fibroblast-like cells covering the surface of bone (known as bone lining cells), osteoblast precursors, and canopy cells (Delaisse, 2014; Sims and Martin, 2014; Lassen et al., 2017; Pirapaharan et al., 2019).

The fourth phase of the bone remodeling cycle is ‘formation,’ when mononucleate osteoblast cells synthesize new bone organic matrix formed by collagen fibers and non-collagenous proteins (e.g., bone sialoprotein, osteopontin, osteocalcin, proteoglycans) that later becomes surrounded and impregnated with mineral deposit mainly in the form of calcium hydroxyapatite. A summary of osteoblastogenesis, the roles played by osteoblasts during this last phase, and the fate of osteoblasts is described in Table 3.

While bone formation surpasses resorption during childhood, bone formation and resorption are in balance during young adulthood. However, an unbalanced bone loss occurs with aging (Datta et al., 2008; Rauner et al., 2012; Brandi and Piscitelli, 2013) and could predispose an individual to skeletal disorders including: (i) inflammatory bone loss in periodontal disease, (ii) arthritis (stimulation of bone resorption and inhibition of bone formation by prostaglandins and cytokines), (iii) osteoporosis (bone resorption outpaces bone formation), (iv) hyperparathyroidism and hyperthyroidism (greatly increased rate of bone resorption and formation), (v) Paget’s disease (increased and abnormal [shape, weakness, and brittleness] bone formation), (vi) osteomalacia (delayed/defficient bone mineralization), and (vi) osteopetrosis (failure of osteoclasts to resorb bone) (Roodman et al., 1992; Delmas, 1995; Gallagher, 1997; Mills and Frausto, 1997; Raisz, 1997; Charles and Key, 1998; Schneider et al., 1998; Siris, 1998; Kini and Nandeesh, 2012).

Matrix Metalloproteinases: Modulators of Bone Remodeling

Matrix metalloproteinases are a family of at least 24 highly homologous, multi-domain enzymes (Figure 1) with the capacity to degrade virtually all extracellular matrix components including collagen, aggrecan, elastin, and fibronectin (Lu et al., 2011; Fernandez-Patron et al., 2016).

FIGURE 1

All MMP family members are synthesized as catalytically inactive (latent) pro-enzymes (pro-MMPs) that contain a: signal N-terminal peptide sequence (∼20 amino acids), pro-peptide domain (∼80 amino acids), catalytic domain (approximately 160 amino acids), hinge (linker peptide) region of variable length (10–30 amino acids), and a hemopexin-like C-terminal domain (Hpx) (∼210 amino acids). The smallest MMPs (MMP-7 and MMP-26) lack the hinge and hemopexin domains, and therefore exhibit a reduced affinity for gelatin. MMP-23 has unique domains (such as the cysteine array, IgG-like domain, interleukin-1 type II receptor-like domains) instead of the hemopexin domain (Massova et al., 1998; Pei et al., 2000; Bode and Maskos, 2003; Visse and Nagase, 2003; Nagase et al., 2006; Piccard et al., 2007; Lopez-Otin et al., 2009; Bonnans et al., 2014; Vandooren et al., 2014; Vandenbroucke and Libert, 2014; Cui et al., 2017). The amino-terminal signal peptide targets the pro-MMPs to the rough endoplasmic reticulum, whereas the C-terminus harbors a cysteine residue and a furin cleavage site (PRCGXPD), both of which are important for conversion into the mature, active enzyme (Bonnans et al., 2014). Presence of an intact pro-peptide accounts for the latency of pro-MMPs, which can be overriden through the activation of a “cysteine-switch” mechanism (Van Wart and Birkedal-Hansen, 1990). The pro-peptide contains a cysteine residue that prevents catalytic activity when it is coordinated with a Zn(II)-ion in the catalytic domain (Springman et al., 1990; Van Wart and Birkedal-Hansen, 1990). The cysteine-Zn(II) interaction can be disrupted by alkylating compounds such as the organomercurial 4-aminophenylmercuric acetate as well as by serine proteases and other MMPs such as membrane-type MMPs, which act at the cell surface to which they anchor through their transmembrane domain/short cytoplasmic tail or by glycosylphosphatidylinositol linkage (Bonnans et al., 2014). MMP autolysis is another mechanism of activation mediated by allosteric perturbation of the inactive proenzyme (Springman et al., 1990; Van Wart and Birkedal-Hansen, 1990; Pei and Weiss, 1995; Pei et al., 2000; Meng et al., 2016). The catalytic domain harbors the Zn(II)-binding motif HEXXHXXGXXH, a catalytic Zn(II), a structural Zn(II), specific pockets related to specificity (S1, S2,…Sn and S1′, S2′,…Sn′) and coordinated Ca(II) ions which confer stabilization. The catalytic Zn(II) is coordinated by three histidine residues (Bode and Maskos, 2003; Bonnans et al., 2014; Vandenbroucke and Libert, 2014). The hinge domain is flexible and mediates interactions with substrates, cell-surface proteins, and tissue inhibitors (Cui et al., 2017; Liu and Khalil, 2017). The hemopexin domain modulates substrate recognition and specificity, binding to cell-surface receptors and inhibitors, activation of MMPs, and cellular MMP internalization for degradation (Visse and Nagase, 2003; Nagase et al., 2006; Piccard et al., 2007).

Matrix metalloproteinases expression and activity are tightly regulated at various levels: gene transcription, translation and secretion of the inactive enzyme precursor, proteolytic activation of the zymogen, spatial localization, interaction with specific extracellular matrix proteins, and inhibition by endogenous inhibitors (such as tissue inhibitors of MMPs [TIMPs 1-4], α2-macroglobulin, and human fibrinogen) (Sottrup-Jensen, 1989; Overall et al., 1991; Kusano et al., 1998; Zeng et al., 1998; Sternlicht and Werb, 2001; Han et al., 2003; Greenlee et al., 2007; Clark et al., 2008; Fanjul-Fernandez et al., 2010; Hadler-Olsen et al., 2011; Arpino et al., 2015; Sarker et al., 2019). Despite their similar names, TIMPs 1-4 exhibit large differences in their primary sequence, tissue expression, transcriptional regulation and in their inhibitory spectrum (Brew et al., 2000). In bone, TIMP-2 and TIMP-3, unlike TIMP-1, are effective inhibitors of the membrane-type MMPs (e.g., MMP-14), while TIMP-3 displays the broadest inhibitory actions of all TIMPs against metalloproteinases. Unlike TIMP-1, -2, and -4, which are soluble, TIMP-3 has basic amino acid residues in its C- and N-termini through which TIMP-3 attaches to heparan and chondroitin sulfate in the extracellular matrix and inhibits both MMPs and members of ‘a disintegrin and metalloproteinase’ (ADAM) and ‘a disintegrin and metalloproteinase with thrombospondin domains’ (ADAMTS) family including ADAM-17 and ADAMTS-4/-5 (Porter et al., 2005; Javaheri et al., 2016). Deficiency of tissue inhibitors (TIMP-1, -2, or -4) has minor impact on bone phenotype. However, both Timp3 deficiency and transgenic overexpression alters craniofacial bones of endochondral and intramembranous origins in mice, while the growth plates appear normal in these mice (Javaheri et al., 2016). Paradoxically, mice deficient in RECK (an MMP inhibitor anchored on the cell membrane with inhibitory actions against MMP-2, -9, and -14 and ADAM-10) die in utero displaying a perturbed extracellular matrix organization (Javaheri et al., 2016).

These observations suggest that bone remodeling may not be solely defined by the balance/imbalance between MMPs and TIMPs. Rather, other molecules expressed and released in the settings of bone physiology and pathology such as RECK (Paiva and Granjeiro, 2014) and some acute phase reactants (alpha 2-macroglobulin, fibrinogen) may regulate/dysregulate MMP activity in inflammatory conditions thus perturbing the normal bone remodeling process (Cook et al., 2018; Sarker et al., 2019). A consequence implied by the latter notion is that MMPs, ADAMs and ADAMTS molecules may be released from bone or non-bone tissues to influence bone remodeling through autocrine and paracrine actions. In other words, MMPs likely circulate bound to non-classical inhibitors (such as acute phase reactants) being recruited to sites of active bone remodeling, where local substrates act as chemoattractants and local activators (other proteases, reactive oxygen species) activate them.

The aforementioned levels of regulation effectively dissociate MMP expression from MMP activity (e.g., since overexpression of endogenous MMP inhibitors would effectively reduce MMP activity). Current biochemical techniques for assessing MMP activity are non-reliable. However, as research requires a proxy, MMP expression is often used as a surrogate (albeit incorrectly) for MMP activity. There remains an urgent need for highly sensitive, specific, and robust methods for assessing the activity potential of individual MMPs such that therapeutic strategies can be designed to specifically reduce the activity of overactive MMPs (i.e., those whose activity levels are above baseline) or to increase the activity of underactive MMPs (i.e., those whose activity levels are below baseline).

Roles of MMPs Associated to Bone Development and Remodeling

The biochemical actions of MMPs are intimately linked to their cells of origin. Table 4 describes cell-specific roles of MMPs in physiological bone remodeling. Osteoclast-mediated bone resorption in calvaria and long bones requires normal enzymatic activity of MMPs and cysteine proteinases such as cathepsin K whose deficiency impairs bone remodeling (Everts et al., 1999; Delaisse et al., 2003). This is evidenced in osteoclasts from patients with pycnodysostosis (an osteopetrosis-like bone disease related to loss-of-function mutations in the cathepsin K gene) and osteoclasts from cathepsin K-deficient mice which are unable to efficiently digest organic bone matrix, resulting in large, mineral-free areas of bone matrix (Everts et al., 1998, 2009). Cysteine proteinases synthesized and used by the different osteoclasts for bone matrix digestion (Everts et al., 2006) can degrade intramembranous bones as well as osteoclast-derived MMPs (Everts et al., 2009). Cysteine proteinases are secreted to act in the low pH environments formed by osteoclasts in the resorption sites, with MMPs degrading the rest of the bone matrix when the pH increases (Everts et al., 1998) as well as contributing to the digestion of fibrillar, non-mineralized collagen in Howship’s lacunae abandoned by osteoclast cells (Everts et al., 2002). These complementary and overlapping contributions of the MMP and cysteine proteinase families make the process of bone tissue remodeling both complex and robust.

The involvement of MMPs in bone remodeling has become clear with the aid of animal models such as MMP-deficient mice, which show a variety of bone abnormalities (Table 5). Impaired bone tissue remodeling in Mmp2^–/– mice (Table 5, row 2) is characterized by a reduced number of osteoblasts and osteoclasts, disruption of the canicular network exacerbating osteocyte death, disruption of the MMP-2-osteopontin-bone sialoprotein axis, and promotion of osteolysis (Martignetti et al., 2001; Inoue et al., 2006; Mosig et al., 2007; Malaponte et al., 2016). MMP-9-deficient mice show alterations in cartilage-bone replacement during endochondral ossification (Vu et al., 1998) (Table 5, row 3). This phenotype may be explained by an inefficient degradation of the cartilage matrix, which leads to a diminished bioavailability of extracellular matrix-derived vascular endothelial growth factor and consequently effects osteoclasts and endothelial cells movement into the cartilage (Ortega et al., 2010). Bone tissue modeling and remodeling processes are altered in MMP-13 deficient mice (Table 5, row 4) (Inada et al., 2004; Stickens et al., 2004; Ortega et al., 2005). MMP-14 deficiency (Table 5, row 5), which is associated with high lethality, results in the most drastic skeletal phenotype among MMP-deficient mice (Holmbeck et al., 1999; Zhou et al., 2000). Double gene-deficient mice lacking at least one MMP gene have been engineered and their bone phenotype have been studied. For instance, double-knockout mice lacking MMP-2 and uPARAP/Endo180 (endocytic receptor of collagen and collagen fragments for degradation in the lysosomes) show reduced bone mineral density, short long bones, and poor trabecular bone quality (Madsen et al., 2013). MMP-8 and MMP-13 double-deficient mice have abnormal growth plate as well as augmented metaphyseal trabecular bone mineral density (Inada et al., 2001, 2002; Stickens et al., 2004). Double knockout mice lacking MMP-9 and MMP-13 exhibit expanded growth plates, disorganized hypertrophic chondrocyte zone, increased number of end-differentiated hypertrophic cells, and delayed formation of the bone marrow cavity (Kennedy et al., 2005; Paiva and Granjeiro, 2014). The bone phenotype of mice with a double knockout for MMP-14 and MMP-2 reassembles that of MMP-14-deficient mice (Oh et al., 2004). MMP-14 and MMP-16 double-knockout mice develop a bone phenotype that affects ossification (intramembranous and endochondral) and is characterized by severe irregularities, including (i) high mortality associated to developmental defects, (ii) noticeable craniofacial malformations such as cleft palate, thinner cranial vault bones, deficiently developed parietal, as well as frontal and nasal bones, (iii) altered growth plate, and (iv) cortical bone shortening (Paiva and Granjeiro, 2014). MMP-14 and uPARAP/Endo180 double-knockout mice die soon after birth (Wagenaar-Miller et al., 2007). As listed in Table 6, MMP activity contributes to numerous bone pathologies including arthritis, osteoporosis, osteonecrosis, periodontitis, sinonasal osteitis, degenerated lumbar disk tissues, and bone cancer metastasis (Aiken and Khokha, 2010; Koskinen et al., 2011; Mittal et al., 2016; Rose and Kooyman, 2016; Lazarus et al., 2017; Paiva and Granjeiro, 2017; Tauro and Lynch, 2018; Zhang et al., 2018). The roles played by MMPs in these pathologies are influenced by non-matrix proteins such as TIMPs, transforming growth factor, vascular endothelial growth factor, bone morphogenic proteins, activated protein C, and the Wnt [Wingless-type MMTV integration site family]/β-catenin (Table 7).

MMPs as Sheddases

Beyond the direct degradation of extracellular matrix substrates (e.g., collagen), MMP-mediated cleavage of substrates can lead to the release (shedding) into the extracellular matrix of soluble fragments of cell membrane-anchored receptor ligands. This extracellular event enables ligand-mediated activation of cognate receptors and elicits downstream intracellular signal transduction cascades which modify gene transcription and, ultimately, cell behavior. A prominent example pertinent to osteoblasts is the release of RANKL, which is the ligand of receptor activator of nuclear factor kappa B (RANK), by MMP-14. This MMP-14/RANKL/RANK/signal transduction axis regulates osteoblastogenesis and osteoclastogenesis, making MMP-14 crucial for normal bone formation (Bonfil et al., 2007; Thiolloy et al., 2009; Sabbota et al., 2010; Bonfil and Cher, 2011). The ligand shedding activity of MMPs influences the propensity to cancer metastasis and bone disease. For instance, MMP-14-mediated shedding of RANKL and downstream activation of RANK in the left supraclavicular lymph node cells of the prostate stimulates the non-receptor tyrosine kinase, SRC, to effectively increase the migration of prostate tumor cells which can metastasize to bone (Sabbota et al., 2010). Similarly, osteoclast-derived MMP-7 solubilizes osteoblast-bound RANKL whose release into the tumor-bone microenvironment promotes osteoclast activation in bone metastatic sites contributing to prostate and mammary tumor-induced osteolysis (Lynch et al., 2005; Thiolloy et al., 2009).

MMP-Generated Neoepitopes

The proteolytic action of MMPs on extracellular matrix macromolecules can result in the exposure of neo-epitopes (i.e., unique bioactive MMP-generated fragments). Compared to healthy subject controls, patients with ankylosing spondylitis (which is a form of arthritis that causes inflammation of the vertebrae) show significantly higher levels of different neo-epitopes such as C1M, C2M, C3M, C4M, C5M, C6M, and C7M from collagen type I, II, III, IV, V, VI, and VII (Veidal et al., 2012; Genovese and Karsdal, 2016). Some of these neo-epitopes have been combined (e.g., C2M, C3M, and C6M) for diagnostic purposes (Bay-Jensen et al., 2012). IPEN341-342FFGV is an MMP cleavage site which could be useful as diagnostic and prognostic makers for osteoarthritis (Bay-Jensen et al., 2011). Similarly, other MMP-generated neo-epitopes derived from collagen type II (e.g., C2C, C2M, C-terminal telopeptide of type II collagen (CTX-II), and TIINE) hold biomarker potential for osteoarthritis (Karsdal et al., 2010; Qvist et al., 2010; Karsdal et al., 2011).

Over-Overexpression of MMPs

Over-expression of MMPs is frequently reported in arthritis (Burrage et al., 2006; Tokito and Jougasaki, 2016). Collagenolytic MMPs (such as MMP-1, -2, -8, -13, and -14) are expressed in the arthritic joint and likely participate in the degradation of cartilage type II collagen, while MMP-3, -7, and -9 can degrade aggrecan leading to joint destruction (Puliti et al., 2012; Tokito and Jougasaki, 2016). Such a pathological mechanism has been proposed for MMP-3 and MMP-13 in degenerative joint disease in the elderly (Neuhold et al., 2001; Troeberg and Nagase, 2012; Jackson et al., 2014; Pap and Korb-Pap, 2015). Other contributions to osteoarthritis from activities related to MMP-3 include MMP-3-mediated activation of MMP-1 and MMP-13 (Mancini and di Battista, 2006; Tokito and Jougasaki, 2016). In rheumatoid arthritis, MMP-14 is greatly expressed in fibroblast-like synoviocytes and macrophages, and it could be an effector to cartilage destruction (Pap et al., 2000; Sabeh et al., 2010). MMP-1 and MMP-3 likely participate in cartilage destruction in rheumatoid arthritis and osteoarthritis (Burrage et al., 2006; Fiedorczyk et al., 2006; Tokito and Jougasaki, 2016). As a result, MMP overexpression could be therapeutically targeted in arthritis (Tokito and Jougasaki, 2016). Whether reducing MMP expression (or activity) levels provides a clinical benefit is unclear. In experimental models, many synthetic MMP inhibitors have shown positive effects (Ishikawa et al., 2005). At the clinical level, however, all efforts with MMP inhibitors to block the damaging activity of MMPs in arthritis and other non-neoplastic conditions were regrettably unsuccessful (Burrage et al., 2006; Tokito and Jougasaki, 2016). Reasons for these failures include: (i) deficient clinical trial designs (Burrage et al., 2006), (ii) unwanted characteristics of MMP inhibitors (side effects including musculoskeletal pain, low oral bioavailability, short in vivo half-lives, and lack of selectivity [Iyer et al., 2012; Fields, 2015; Tokito and Jougasaki, 2016]), (iii) inability of MMP inhibitors to infiltrate the cartilage/bone/synovial interface (Burrage et al., 2006), (iv) neglect of the highly complex functions served by MMPs in physiological and disease states (Iyer et al., 2012; Li et al., 2013; Sawicki, 2013) and (v) broad tissue distribution and substrate promiscuity exhibited by MMPs and their substrates (Burrage et al., 2006; Tokito and Jougasaki, 2016). To date, there remains a need for highly selective MMP inhibitors and for better information on the disease-specific substrates, which could be therapeutically targeted as shown by recent studies with MMP-13 in osteoarthritis (Li et al., 2011) as well as for more efficient and reliable techniques to sensitively measure condition-specific MMP activity potential (not just MMP expression levels).

MMP Gene Polymorphism

A nucleotide polymorphism, by which an additional guanine creates an ETS transcription factor binding site (5′-GGA-3′) at position 1607 in the promoter sequence of the MMP-1 gene, has been related to bone mineral density (BMD) (Rutter et al., 1998). This polymorphism is associated with increased transcription of the MMP-1 gene and elevated MMP-1 activity. Among 819 postmenopausal Japanese women, BMD (e.g., D50, D100) for the distal radius had a lower value in women with the GG/GG genotype (47.9%) than in those with other (e.g., G/GG [41.9%], G/G [10.3%], G/G + G/GG [52.1%]) genotypes. A -1562C3 thymine polymorphism in the MMP-9 gene has been related to BMD in a population-based study (1114 Japanese men and 1087 women). It seems that the T allele (e.g., in men with CT or TT genotypes) of MMP-9, which shows greater transcriptional activity than the C allele (e.g., in men with CC genotype), is linked to decreased bone mass, and has a predominant effect on BMD (Zhang et al., 1999; Yamada et al., 2004). A single nucleotide polymorphism rs17576 may be involved in the pathogenesis of lumbar disk herniation (Jing et al., 2018); while the G allele of rs17576 appears to correlate with more severe stages of disk degeneration.

MMP Deficiency and Insufficiency in Humans

Having discussed the roles of MMPs under physiological and pathological conditions, we will next discuss how their deficiency and insufficiency relates to bone metabolic abnormalities.

MMP-2 gene deficiency leads to a rare human skeletal disorder¹, which was first reported in consanguineous Saudi Arabian families, and is characterized by severe bone alterations (Martignetti et al., 2001). Osteolytic and metabolic changes linked to MMP-2 deficiency affect tarsal, carpal, and phalangeal bones, cause severe arthropathy, osteoporosis, fibrous nodules, distinctive craniofacial defects such as exophthalmos, brachycephaly, and flattened nasal bridges and dwarfism (Al-Aqeel et al., 2000; Al-Mayouf et al., 2000; Al-Aqeel, 2005; Mosig et al., 2007; Page-McCaw et al., 2007; Castberg et al., 2013). This complex syndrome is currently categorized as a form of Torg syndrome and results from homoallelic mutations in the gene for MMP-2 located at 16q12-21 (Martignetti et al., 2001; Liang et al., 2016). A Tyr codon in the MMP-2 prodomain is replaced with the Y244X stop codon and an Arg is replaced with a His (R101H) in the cysteine-containing domain (PRCGNPD substituted by PHCGNPD). The R101H mutation is suggested to perturb coordination of Cys102 to the catalytic Zn(II) domain, consequently activating intracellular pro-MMP-2 and leading to its auto-degradation (Kennedy et al., 2005; Krane and Inada, 2008). A homoallelic missense mutation in the catalytic Zn(II) domain (E404K) has been revealed in Winchester syndrome (another variant of multicentric osteolysis) (Zankl et al., 2005). These rare Torg and Winchester arthritic syndromes together with others (such as multicentric osteolysis with nodulosis and arthropathy [known as MONA]) belong to a general family of hereditary autosomal dominant and recessive skeletal disorders with progressive bone loss and joint destruction (Al-Mayouf et al., 2000; Martignetti et al., 2001; Al-Aqeel, 2005; Zankl et al., 2005; Rouzier et al., 2006; Mosig et al., 2007; Tuysuz et al., 2009).

Similar to MMP-2, a homozygous dominant mutation (Ser substituted by Phe [F56S]) in the pro-region domain of MMP-13 also results in a bone development disorder known as spondyloepimetaphyseal dysplasia-Missouri type (Kennedy et al., 2005)². This disorder, which appears to spontaneously resolve by adolescence, is characterized by anomalous modeling of long bones, mild defects in epiphysis, moderate to severe changes in the metaphysis morphology, pear-shaped vertebrae, femoral and tibial bowing, genu varum deformities, and osteoarthritis. While the biochemical mechanisms linking MMP-13 to these bone abnormalities remain unclear, the phenotype of MMP-13 deficiency could be due to a late exit of chondrocyte cells from the growth plate (Kennedy et al., 2005).

MMP-14 is widely considered one of the physiological activators of MMP-2 as it converts pro-MMP-2 into mature MMP-2 at the cell surface (Fernandez-Patron et al., 2016). An MMP-14 homoallelic mutation (T > R replacement in the signal peptide domain) destabilizes the interaction (e.g., recognition and binding) of the MMP-14 signal peptide with the signal recognition particle complex, thus affecting MMP-14 targeting to the plasma membrane (Evans et al., 2012). This MMP-14 homoallelic mutation causes an apparent deficiency of biochemically active MMP-14 at the cell membrane which impairs pro-MMP-2 activation and causes a condition of MMP-2 activity deficiency with Winchester syndrome (Evans et al., 2012)³.

A missense homozygous mutation (g.16250T > A, which replaces His226 of the Zn(II) catalytic domain with Gln [p.H226Q]), in the MMP20 gene disrupts the metal-binding site and prevents MMP-20 proteolytic activity regarding enamel matrix proteins (Ozdemir et al., 2005)⁴. This mutation may lead to autosomal-recessive hypomaturation amelogenesis imperfecta, a group of inherited heterogeneous diseases that alter enamel development (amount, composition, structure) in humans (Kim J.W. et al., 2005). Another mutation in the intron 6 splice acceptor (g.30561A > T) that causes this disease is specifically characterized by pigmented teeth with a mottled and rough surface (Kim J.W. et al., 2005).

Partial loss of MMP activity or impaired MMP secretion can lead to MMP activity insufficiency. A pervasive cause of MMP insufficiency can be medications with such MMP inhibitory actions including: (i) Statins (200 million prescriptions in the United States/year; 14 million prescriptions for lovastatin alone in 2014)⁵ which can cause myositis and rhabdomyolysis (Luan et al., 2003; Thompson et al., 2003). (ii) Doxycycline (7 million prescriptions in 2014)⁵ with side-effects including joint inflammation in humans and cardiac inflammation in mice (Berry et al., 2015). (iii) Therapeutic antibodies against MMPs and MMP inhibitor drugs for treating patients with rheumatoid arthritis, severely active Crohn’s disease, and cystic fibrosis⁶. If these antibodies reduce MMP activity below baseline levels, they would cause MMP insufficiency with unpredictable consequences. Pharmacological MMP-inhibitors in Phase 3 clinical trials conducted during 1997 and 1998 in patients with advanced cancers led to an as of yet poorly understood, very severe inflammatory musculoskeletal syndrome (Zucker et al., 2000; Coussens et al., 2002). Another common cause of MMP insufficiency could be the pathological elevation of endogenous MMP inhibitors (e.g., tissue inhibitors of MMPs, α-2-macroglobulin, RECK) (Mott et al., 2000; Oh et al., 2001; Nagase et al., 2006; Klein and Bischoff, 2011). In addition, there is fibrinogen, an acute phase reactant in arthritis, which our laboratory discovered recently to inhibit MMP-2 in a cohort of rheumatoid arthritis patients (Sarker et al., 2019).

Summary

In summary, bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts are responsible for constant bone tissue remodeling (Figure 2). The activation of this multicellular unit and the intense communication between the bone cells is tightly regulated by mechanical stimuli, apoptosis, as well as systemic and local factors such as hormones and cytokines including RANKL, CSF-M, IL-3, and IL-6. Proteases of the MMP and cysteine proteinase families converge in the modulation of bone remodeling. Whereas proteolytic activity has long been thought to be required for the degradation of bone tissue in osteoarthritis and osteoporosis, inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. Thus, there remains a need to rethink the role played by proteases in bone physiology and pathology. More specific information related to bone remodeling and presumed pathways by which proteases, in particular MMPs, contribute to bone tissue remodeling in health and disease is provided in previous excellent reviews (Kini and Nandeesh, 2012; Rauner et al., 2012; Hienz et al., 2015; Liang et al., 2016; Mittal et al., 2016; Franco et al., 2017; Paiva and Granjeiro, 2017; Tauro and Lynch, 2018; Plotkin and Bruzzaniti, 2019).

FIGURE 2

References

• 1

  AgnihotriR.CrawfordH. C.HaroH.MatrisianL. M.HavrdaM. C.LiawL. (2001). Osteopontin, a novel substrate for matrix metalloproteinase-3 (Stromelysin-1) and matrix metalloproteinase-7 (Matrilysin).J. Biol. Chem.27628261–28267. 10.1074/jbc.m103608200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AguirreJ. I.PlotkinL. I.StewartS. A.WeinsteinR. S.ParfittA. M.ManolagasS. C.et al (2006). Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss.J. Bone Miner. Res.21605–615. 10.1359/jbmr.060107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AhrensD.KochA. E.PopeR. M.Stein-PicarellaM.NiedbalaM. J. (1996). Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis.Arthritis Rheum.391576–1587. 10.1002/art.1780390919

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  AikenA.KhokhaR. (2010). Unraveling metalloproteinase function in skeletal biology and disease using genetically altered mice.Biochim. Biophys. Acta1803121–132. 10.1016/j.bbamcr.2009.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  Al-AqeelA.Al SewairiW.EdressB.GorlinR. J.DesnickR. J.MartignettiJ. A. (2000). Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.Am. J. Med. Genet.9311–18. 10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  Al-AqeelA. I. (2005). Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. The first genetic defect of matrix metalloproteinase 2 gene.Saudi Med. J.2624–30.

  • Pubmed Abstract
  • Google Scholar

• 7

  AlfordA. I.JacobsC. R.DonahueH. J. (2003). Oscillating fluid flow regulates gap junction communication in osteocytic MLO-Y4 cells by an ERK1/2 MAP kinase-dependent mechanism.Bone3364–70. 10.1016/s8756-3282(03)00167-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  AllistonT. (2014). Biological regulation of bone quality.Curr. Osteoporos. Rep.12366–375. 10.1007/s11914-014-0213-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  AlmalkiS. G.AgrawalD. K. (2016). Effects of matrix metalloproteinases on the fate of mesenchymal stem cells.Stem Cell. Res. Ther.71–12. 10.1186/s13287-016-0393-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  Al-MayoufS. M.MajeedM.HugossonC.BahabriS. (2000). New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.Am. J. Med. Genet.935–10. 10.1002/1096-8628(20000703)93:1<5::aid-ajmg2>3.0.co;2-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  AndersenT. L.AbdelgawadM. E.KristensenH. B.HaugeE. M.RolighedL.BollerslevJ.et al (2013). Understanding coupling between bone resorption and formation: are reversal cells the missing link?Am. J. Pathol.183235–246. 10.1016/j.ajpath.2013.03.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  ApteS. S.FukaiN.BeierD. R.OlsenB. R. (1997). The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis.J. Biol. Chem.27225511–25517. 10.1074/jbc.272.41.25511

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  ArpinoV.BrockM.GillS. E. (2015). The role of TIMPs in regulation of extracellular matrix proteolysis.Matrix Biol.4247–254. 10.1016/j.matbio.2015.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  ArumugamB.VairamaniM.PartridgeN. C.SelvamuruganN. (2018). Characterization of Runx2 phosphorylation sites required for TGF-β1-mediated stimulation of matrix metalloproteinase-13 expression in osteoblastic cells.J. Cell Physiol.2331082–1094. 10.1002/jcp.25964

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  ArumugamB.VishalM.ShreyaS.MalavikaD.RajpriyaV.HeZ.et al (2019). Parathyroid hormone-stimulation of Runx2 during osteoblast differentiation via the regulation of lnc-SUPT3H-1:16 (RUNX2-AS1:32) and miR-6797-5p.Biochimie15843–52. 10.1016/j.biochi.2018.12.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  BalemansW.PitersE.CleirenE.AiM.Van WesenbeeckL.WarmanM. L.et al (2008). The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations.Calcif. Tissue Int.82445–453. 10.1007/s00223-008-9130-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  BaloochG.BaloochM.NallaR. K.SchillingS.FilvaroffE. H.MarshallG. W.et al (2005). TGF-beta regulates the mechanical properties and composition of bone matrix.Proc. Natl. Acad. Sci. U.S.A.10218813–18818. 10.1073/pnas.0507417102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  BaronR. (1989). Molecular mechanisms of bone resorption by the osteoclast.Anat. Rec.224317–324. 10.1002/ar.1092240220

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  Bar-ShavitZ. (2007). Theosteoclast: amultinucleated, hematopoieticorigin, bone-resorbing osteoimmune cell.J. Cell Biochem.1021130–1139. 10.1002/jcb.21553

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  BarthelemiS.RobinetJ.GarnotelR.AntonicelliF.SchittlyE.HornebeckW.et al (2012). Mechanical forces-induced human osteoblasts differentiation involves MMP-2/MMP-13/MT1-MMP proteolytic cascade.J. Cell Biochem.113760–772. 10.1002/jcb.23401

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  Bay-JensenA. C.LeemingD. J.KleyerA.VeidalS. S.SchettG.KarsdalM. A. (2012). Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study.Rheumatol. Int.323565–3572. 10.1007/s00296-011-2237-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  Bay-JensenA. C.LiuQ.ByrjalsenI.LiY.WangJ.PedersenC.et al (2011). Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM–increased serum CIIM in subjects with severe radiographic osteoarthritis.Clin. Biochem.44423–429. 10.1016/j.clinbiochem.2011.01.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  BaylinkD. J.FinkelmanR. D.MohanS. (1993). Growth factors to stimulate bone formation.J. Bone. Miner. Res.8565–572.

  • Pubmed Abstract
  • Google Scholar

• 24

  BellidoT. (2014). Osteocyte-driven bone remodeling.Calcif. Tissue Int.9425–34. 10.1007/s00223-013-9774-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  BellidoT.GallantK. M. H. (2019). “Hormonal effects on bone cells,” in Basic and Applied Bone Biology, edsBurrD. B.AllenM. R., (Cambridge, MA: Academic Press), 299–314. 10.1016/b978-0-12-416015-6.00015-0

  • CrossRef
  • Google Scholar

• 26

  BellidoT.PlotkinL. I.BruzzanitiA. (2019). “Bone cells,” in Basic and Applied Bone Biology, edsBurrD. B.AllenM. R., (Cambridge, MA: Academic Press), 37–55.

  • Google Scholar

• 27

  BergersG.BrekkenR.McMahonG.VuT. H.ItohT.TamakiK.et al (2000). Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.Nat. Cell. Biol.2737–744. 10.1038/35036374

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  BerryE.Hernandez-AnzaldoS.GhomashchiF.LehnerR.MurakamiM.GelbM. H.et al (2015). Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever.J. Am. Heart. Assoc.41–22. 10.1161/JAHA.115.001868

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BlairH. C.TeitelbaumS. L.GhiselliR.GluckS. (1989). Osteoclastic bone resorption by a polarized vacuolar proton pump.Science245855–857. 10.1126/science.2528207

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  BlavierL.DelaisseJ. M. (1995). Matrix metalloproteinases are obligatory for the migration of preosteoclasts to the developing marrow cavity of primitive long bones.J. Cell Sci.1083649–3659.

  • Pubmed Abstract
  • Google Scholar

• 31

  BodeW.MaskosK. (2003). Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.Biol. Chem.384863–872.

  • Pubmed Abstract
  • Google Scholar

• 32

  BodineP. V.KommB. S. (2006). Wnt signaling and osteoblastogenesis.Rev. Endocr. Metab. Disord.733–39. 10.1007/s11154-006-9002-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  BonewaldL. F. (2011). The amazing osteocyte.J. Bone Miner. Res.26229–238. 10.1002/jbmr.320

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  BonewaldL. F.JohnsonM. L. (2008). Osteocytes, mechanosensing and Wnt signaling.Bone42606–615. 10.1016/j.bone.2007.12.224

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  BonewaldL. F.MundyG. R. (1990). Role of transforming growth factor-beta in bone remodeling.Clin. Orthop. Relat. Res.250261–276.

  • Pubmed Abstract
  • Google Scholar

• 36

  BonfilR. D.CherM. L. (2011). The role of proteolytic enzymes in metastatic bone disease.IBMS BoneKEy816–36. 10.1138/20110487

  • CrossRef
  • Google Scholar

• 37

  BonfilR. D.DongZ.Trindade FilhoJ. C.SabbotaA.OsenkowskiP.NabhaS.et al (2007). Prostate cancer-associated membrane type 1-matrix metalloproteinase: a pivotal role in bone response and intraosseous tumor growth.Am. J. Pathol.1702100–2111.

  • Pubmed Abstract
  • Google Scholar

• 38

  BonnansC.ChouJ.WerbZ. (2014). Remodelling the extracellular matrix in development and disease.Nature Rev. Mol. Cell. Biol.15786–801. 10.1038/nrm3904

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  BordS.HornerA.BeetonC. A.HembryR. M.CompstonJ. E. (1999). Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) distribution in normal and pathological human bone.Bone24229–235. 10.1016/s8756-3282(98)00174-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  BordS.HornerA.HembryR. M.CompstonJ. E. (1998). Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development.Bone237–12. 10.1016/s8756-3282(98)00064-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  BordS.HornerA.HembryR. M.ReynoldsJ. J.CompstonJ. E. (1996). Production of collagenase by human osteoblasts and osteoclasts in vivo.Bone1935–40. 10.1016/8756-3282(96)00106-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  BoydenL. M.MaoJ.BelskyJ.MitznerL.FarhiA.MitnickM. A.et al (2002). High bone density due to a mutation in LDL receptor related protein 5.N. Engl. J. Med.3461513–1521. 10.1056/nejmoa013444

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  BoyleW. J.SimonetW. S.LaceyD. L. (2003). Osteoclast differentiation and activation.Nature423337–342. 10.1038/nature01658

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  BrandiM. L.PiscitelliP. (2013). “Epidemiology of osteoporosis and fragility fractures,” in Osteoporosis and Bone Densitometry Measurements, ed.GuglielmiG., (Berlin: Springer-Verlag), 1–4. 10.1007/174_2012_747

  • CrossRef
  • Google Scholar

• 45

  BrewK.DinakarpandianD.NagaseH. (2000). Tissue inhibitors of metalloproteinases: evolution, structure and function.Biochim. Biophys. Acta1477267–283. 10.1016/s0167-4838(99)00279-4

  • CrossRef
  • Google Scholar

• 46

  BruzzanitiA.BaronR. (2006). Molecular regulation of osteoclast activity.Rev. Endocr. Metab. Disord.7123–139. 10.1007/s11154-006-9009-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  Buisson-LegendreN.SmithS.MarchL.JacksonC. (2004). Elevation of activated protein C in synovial joints in rheumatoid arthritis and its correlation with matrix metalloproteinase 2.Arthritis Rheum.502151–2156. 10.1002/art.20313

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  BurgerE. H.Klein-NulendJ. (1999). Mechanotransduction in bone-role of the laculocanalicular network.FASEB13S101–S112.

  • Pubmed Abstract
  • Google Scholar

• 49

  BurrageP. S.MixK. S.BrinckerhoffC. E. (2006). Matrix metalloproteinases: role in arthritis.Front. Biosci.11:529–543.

  • Pubmed Abstract
  • Google Scholar

• 50

  CanalisE. (2009). Growth factor control of bone mass.J. Cell Biochem.108769–777. 10.1002/jcb.22322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  CanalisE.EconomidesA. N.GazzerroE. (2003). Bone morphogenetic proteins, their antagonists, and the skeleton.Endocr. Rev.24218–235. 10.1210/er.2002-0023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  CastbergF. C.KjaergaardS.MosigR. A.LoblM.MartignettiC.MartignettiJ. A.et al (2013). Multicentric osteolysis with nodulosis and arthropathy (MONA) with cardiac malformation, mimicking polyarticular juvenile idiopathic arthritis: case report and literature review.Eur. J. Pediatr.1721657–1663. 10.1007/s00431-013-2102-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  CavallaF.Hernandez-RiosP.SorsaT.BiguettiC.HernandezM. (2017). Matrix metalloproteinases as regulators of periodontal inflammation.Int. J. Mol. Sci.18:440. 10.3390/ijms18020440

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  CharlesJ. M.KeyL. L. (1998). Developmental spectrum of children with congenital osteopetrosis.J. Pediatr.132371–374. 10.1016/s0022-3476(98)70467-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  ChellaiahM. A.MaT. (2013). Membrane localization of membrane type 1 matrix metalloproteinase by CD44 regulates the activation of pro-matrix metalloproteinase 9 in osteoclasts.Biomed. Res. Int.2013:302392. 10.1155/2013/302392

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  ChenD.XieR.ShuB.LandayA. L.WeiC.ReiserJ.et al (2019). Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging.Ann. N. Y. Acad. Sci.144248–60. 10.1111/nyas.13945

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  ChenM.ZhuM.AwadH.LiT. F.SheuT. J.BoyceB. F.et al (2008). Inhibition of beta-catenin signaling causes defects in postnatal cartilage development.J. Cell Sci.1211455–1465. 10.1242/jcs.020362

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  ChenX.WangL.ZhaoK.WangH. (2018). Osteocytogenesis: roles of physicochemical factors, collagen cleavage, and exogenous molecules.Tissue Eng. Part B Rev.24215–225. 10.1089/ten.teb.2017.0378

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  ChoiY. A.KangS. S.JinE. J. (2009). BMP-2 treatment of C3H10T1/2 mesenchymal cells blocks MMP-9 activity during chondrocyte commitment.Cell Biol. Int.33887–892. 10.1016/j.cellbi.2009.04.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  CivitelliR. (2008). Cell-cell communication in the osteoblast/osteocyte lineage.Arch. Biochem. Biophys.473188–192. 10.1016/j.abb.2008.04.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  ClarkI. M.SwinglerT. E.SampieriC. L.EdwardsD. R. (2008). The regulation of matrix metalloproteinases and their inhibitors.Int. J. Biochem. Cell Biol.401362–1378. 10.1016/j.biocel.2007.12.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  CoenG.BallantiP.SilvestriniG.MantellaD.ManniM.Di GiulioS.et al (2009). Immunohistochemical localization and mRNA expression of matrix Glaprotein and fetuin-A in bone biopsies of hemodialysis patients.Virchows Arch.454263–271. 10.1007/s00428-008-0724-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  CohickW. S.ClemmonsD. R. (1993). The insulin-like growth factors.Annu. Rev. Physiol.55131–153.

  • Pubmed Abstract
  • Google Scholar

• 64

  CompstonJ. E. (2001). Sex steroids and bone.Physiol. Rev.81419–447.

  • Pubmed Abstract
  • Google Scholar

• 65

  CookR.SarkerH.Fernandez-PatronC. (2018). Pathologies of matrix metalloproteinase-2 underactivity: A perspective on a neglected condition.Can. J. Physiol. Pharmacol.971–7. 10.1139/cjpp-2018-0525

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  CoussensL. M.FingletonB.MatrisianL. M. (2002). Matrix metalloproteinase inhibitors and cancer: trials and tribulations.Science2952387–2392. 10.1126/science.1067100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  CoxJ. H.StarrA. E.KappelhoffR.YanR.RobertsC. R.OverallC. M. (2010). Matrix metalloproteinase 8 deficiency in mice exacerbates inflammatory arthritis through delayed neutrophil apoptosis and reduced caspase 11 expression.Arthritis Rheum.623645–3655. 10.1002/art.27757

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  CrottiT. N.FlanneryM.WalshN. C.FlemingJ. D.GoldringS. R.McHughK. P. (2006). NFATc1 regulation of the human beta3 integrin promoter in osteoclast differentiation.Gene37292–102. 10.1016/j.gene.2005.12.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  CrottiT. N.SharmaS. M.FlemingJ. D.FlanneryM. R.OstrowskiM. C.GoldringS. R.et al (2008). PU.1 and NFATc1 mediate osteoclastic induction of the mouse β3 integrin promoter.J. Cell Physiol.215636–644. 10.1002/jcp.21344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  CuiN.HuM.KhalilR. A. (2017). Biochemical and biological attributes of matrix metalloproteinases.Prog. Mol. Biol. Transl. Sci.1471–73. 10.1016/bs.pmbts.2017.02.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  DaiJ. C.HeP.ChenX.GreenfieldE. M. (2006). TNF alpha and PTH utilize distinct mechanisms to induce IL-6 and RANKL expression with markedly different kinetics.Bone38509–520. 10.1016/j.bone.2005.10.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  DallasS. L.MiyazonoK.SkerryT. M.MundyG. R.BonewaldL. F. (1995). Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein.J. Cell. Biol.131539–549. 10.1083/jcb.131.2.539

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  DallasS. L.PrideauxM.BonewaldL. F. (2013). The osteocyte: an endocrine cell and more.Endocr. Rev.34658–690. 10.1210/er.2012-1026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  D’AngeloM.BillingsP. C.PacificiM.LeboyP. S.KirschT. (2001). Authentic matrix vesicles contain active metalloproteases (MMP): a role for matrix vesicle-associated MMP-13 in activation of transforming growth factor-beta.J. Biol. Chem.27611347–11353. 10.1074/jbc.m009725200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  DattaH. K.NgW. F.WalkerJ. A.TuckS. P.VaranasiS. S. (2008). The cell biology of bone metabolism.J. Clin. Pathol.61577–587. 10.1136/jcp.2007.048868

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  DelaisseJ. M. (2014). The reversal phase of the bone-remodeling cycle: cellular prerequisites for coupling resorption and formation.Bonekey Rep.3:561. 10.1038/bonekey.2014.56

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  DelaisseJ. M.AndersenT. L.EngsigM. T.HenriksenK.TroenT.BlavierL. (2003). Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities.Microsc. Res. Tech.61504–513. 10.1002/jemt.10374

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  DelmasP. D. (1995). “Biochemical markers for the assessment of bone turnover,” in Osteoporosis: Etiology, Diagnosis, and Management, 2nd Edn, edsRiggsB.MeltonL. J., (Philadelphia: Lippincott-Raven), 319–333.

  • Google Scholar

• 79

  DempsterD. W.CosmanF.ParisienM.ShenV.LindsayR. (1993). Anabolic actions of parathyroid hormone on bone.Endocr. Rev.14690–709. 10.1210/er.14.6.690

  • CrossRef
  • Google Scholar

• 80

  DucyP.SchinkeT.KarsentyG. (2000). The osteoblast: a sophisticated fibroblast under central surveillance.Science2891501–1504. 10.1126/science.289.5484.1501

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  DuerrS.StremmeS.SoederS.BauB.AignerT. (2004). MMP-2/gelatinase A is a gene product of human adult articular chondrocytes and is increased in osteoarthritic cartilage.Clin. Exp. Rheumatol.22603–608.

  • Pubmed Abstract
  • Google Scholar

• 82

  DurieB. G. M.KatzM.CrowleyJ. (2005). Osteonecrosis of the jaw and bisphosphonates.N. Engl. J. Med.35399–102.

  • Google Scholar

• 83

  EgeaV.ZahlerS.RiethN.NethP.PoppT.KeheK.et al (2012). Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling.Proc. Natl. Acad. Sci. U.S.A.109E309–E316. 10.1073/pnas.1115083109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  EijkenM.HewisonM.CooperM. S.de JongF. H.ChibaH.StewartP. M.et al (2005). 11beta-Hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation.Mol. Endocrinol.19621–631. 10.1210/me.2004-0212

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  EngsigM. T.ChenQ. J.VuT. H.PedersenA. C.TherkidsenB.LundL. R.et al (2000). Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones.J. Cell Biol.151879–889.

  • Pubmed Abstract
  • Google Scholar

• 86

  EvansB. R.MosigR. A.LoblM.MartignettiC. R.CamachoC.Grum-TokarsV.et al (2012). Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease winchester syndrome.Am. J. Hum. Genet.91572–576. 10.1016/j.ajhg.2012.07.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  EvertsV.de VriesT. J.HelfrichM. H. (2009). Osteoclast heterogeneity: lessons from osteopetrosis and inflammatory conditions.Biochim. Biophys. Acta1792757–765. 10.1016/j.bbadis.2009.05.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  EvertsV.DelaisséJ. M.KorperW.BeertsenW. (1998). Cysteine proteinases and matrix metalloproteinases play distinct roles in the subosteoclastic resorption zone.J. Bone Miner. Res.131420–1430. 10.1359/jbmr.1998.13.9.1420

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  EvertsV.DelaisséJ. M.KorperW.JansenD. C.Tigchelaar-GutterW.SaftigP.et al (2002). The bone lining cell: its role in cleaning Howship’s lacunae and initiating bone formation.J. Bone Miner. Res.1777–90. 10.1359/jbmr.2002.17.1.77

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  EvertsV.DelaisseJ. M.KorperW.NiehofA.VaesG.BeertsenW. (1992). Degradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases.J. Cell Physiol.150221–231. 10.1002/jcp.1041500202

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  EvertsV.KorperW.HoebenK. A.JansenI. D.BrommeD.CleutjensK. B.et al (2006). Osteoclastic bone degradation and the role of different cysteine proteinases and matrix metalloproteinases: differences between calvaria and long bone.J. Bone Miner. Res.211399–1408. 10.1359/jbmr.060614

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  EvertsV.KorperW.JansenD. C.SteinfortJ.LammerseI.HeeraS.et al (1999). Functional heterogeneity of osteoclasts: matrix metalloproteinases participate in osteoclastic resorption of calvarial bone but not in resorption of long bone.FASEB J.19991219–1230. 10.1096/fasebj.13.10.1219

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  FaccioR.TeitelbaumS. L.FujikawaK.ChappelJ.ZalloneA.TybulewiczV. L.et al (2005). Vav3 regulates osteoclast function and bone mass.Nat. Med.11284–290. 10.1038/nm1194

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  Fanjul-FernandezM.FolguerasA. R.CabreraS.Lopez-OtinC. (2010). Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models.Biochim. Biophys.18033–19. 10.1016/j.bbamcr.2009.07.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  FengJ. Q.WardL. M.LiuS.LuY.XieY.YuanB.et al (2006). Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.Nat. Genet.381310–1315. 10.1038/ng1905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  Fernandez-PatronC.KassiriZ.LeungD. (2016). Modulation of systemic metabolism by MMP-2: from MMP-2 deficiency in mice to MMP-2 deficiency in patients.Compr. Physiol.61935–1949. 10.1002/cphy.c160010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  FerrerasM.FelborU.LenhardT.OlsenB. R.DelaisseJ. M. (2000). Generation and degradation of human endostatin proteins by various proteinases.FEBS Lett.486247–251. 10.1016/s0014-5793(00)02249-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  FiedorczykM.KlimiukP. A.SierakowskiS.Gindzienska-SieskiewiczE.ChwieckoJ. (2006). Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with early rheumatoid arthritis.J. Rheumatol.331523–1529.

  • Pubmed Abstract
  • Google Scholar

• 99

  FieldsG. B. (2015). New strategies for targeting matrix metalloproteinases.Matrix Biol.4239–246. 10.1016/j.matbio.2015.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  FilantiC.DicksonG. R.Di MartinoD.UliviV.SanguinetiC.RomanoP.et al (2000). The expression of metalloproteinase-2, -9, and -14 and of tissue inhibitors-1 and -2 is developmentally modulated during osteogenesis in vitro, the mature osteoblastic phenotype expressing metalloproteinase-14.J. Bone Miner. Res.152154–2168. 10.1359/jbmr.2000.15.11.2154

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  FioreE.FuscoC.RomeroP.StamenkovicI. (2002). Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity.Oncogene215213–5223. 10.1038/sj.onc.1205684

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  FraherL. (1993). Biochemical markers of bone turnover.Clin. Biochem.26431–432.

  • Google Scholar

• 103

  FrancinP. J.AbotA.GuillaumeC.MoulinD.BianchiA.Gegout-PottieP.et al (2014). Association between adiponectin and cartilage degradation in human osteoarthritis.Osteoarthr. Cartil.22519–526. 10.1016/j.joca.2014.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  FrancoC.PatriciaH. R.TimoS.ClaudiaB.MarcelaH. (2017). Matrix metalloproteinases as regulators of periodontal inflammation.Int. J. Mol. Sci.18:E440. 10.3390/ijms18020440

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  GackS.VallonR.SchmidtJ.GrigoriadisA.TuckermannJ.SchenkelJ.et al (1995). Expression of interstitial collagenase during skeletal development of the mouse is restricted to osteoblast-like cells and hypertrophic chondrocytes.Cell Growth Differ.6759–767.

  • Pubmed Abstract
  • Google Scholar

• 106

  GallagherS. K. (1997). Biochemical markers of bone metabolism as they relate to osteoporosis.MLO29:50.

  • Google Scholar

• 107

  GaoY. Y.LiuB. Q.DuZ. X.ZhangH. Y.NiuX. F.WangH. Q. (2010). Implication of oxygen regulated protein 150 (ORP150) in apoptosis induced by proteasome inhibitors in human thyroid cancer cells.J. Clin. Endocrinol. Metab.95E319–E326. 10.1210/jc.2010-1043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  GearingA. J. H.BeckettP.ChristodoulouM.ChurchillM.ClementsJ. M.CrimminM.et al (1995). Matrix metalloproteinases and processing of pro-TNF-alpha.J. Leukoc. Biol.57774–777.

  • Pubmed Abstract
  • Google Scholar

• 109

  GelbB. D.ShiG. P.ChapmanH. A.DesnickR. J. (1996). Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency.Science2731236–1238. 10.1126/science.273.5279.1236

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  GenoveseF.KarsdalM. A. (2016). Protein degradation fragments as diagnostic and prognostic biomarkers of connective tissue diseases: understanding the extracellular matrix message and implication for current and future serological biomarkers.Expert Rev. Proteomics13213–225. 10.1586/14789450.2016.1134327

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  GeoffroyV.Marty-MorieuxC.Le GoupilN.Clement-LacroixP.TerrazC.FrainM.et al (2004). In vivo inhibition of osteoblastic metalloproteinases leads to increased trabecular bone mass.J. Bone Miner. Res.19811–822. 10.1359/jbmr.040119

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  GongY.SleeR. B.FukaiN.RawadiG.Roman-RomanS.ReginatoA. M.et al (2001). LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.Cell107513–523.

  • Pubmed Abstract
  • Google Scholar

• 113

  GonzaloP.GuadamillasM. C.Hernandez-RiquerM. V.PollanA.Grande-GarcíaA.BartolomeR. A.et al (2010). MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling.Dev. Cell1877–89. 10.1016/j.devcel.2009.11.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  GoriF.HofbauerL. C.DunstanC. R.SpelsbergT. C.KhoslaS.RiggsB. L. (2000). The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated.Endocrinology1414768–4776. 10.1210/endo.141.12.7840

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  GreenleeK. J.WerbZ.KheradmandF. (2007). Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted.Physiol. Rev.8769–98. 10.1152/physrev.00022.2006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  GuY.PrestonM. R.El HajA. J.HowlJ. D.PublicoverS. J. (2001). Three types of K+ currents in murine osteocyte-like cells (MLO-Y4).Bone2829–37. 10.1016/s8756-3282(00)00439-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  GuanC. C.YanM.JiangX. Q.ZhangP.ZhangX. L.LiJ.et al (2009). Sonic hedgehog alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of bone marrow stromal cells.Bone451146–1152. 10.1016/j.bone.2009.08.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  HachemiY.RappA. E.PickeA. K.WeidingerG.IgnatiusA.TuckermannJ. (2018). Molecular mechanisms of glucocorticoids on skeleton and bone regeneration after fracture.J. Mol. Endocrinol.61R75–R90. 10.1530/JME-18-0024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  Hadler-OlsenE.FadnesB.SylteI.Uhlin-HansenL.WinbergJ. O. (2011). Regulation of matrix metalloproteinase activity in health and disease.FEBS J.27828–45. 10.1111/j.1742-4658.2010.07920.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  HaeuslerG.WalterI.HelmreichM.EgerbacherM. (2005). Localization of matrix metalloproteinases, (MMPs) their tissue inhibitors, and vascular endothelial growth factor (VEGF) in growth plates of children and adolescents indicates a role for MMPs in human postnatal growth and skeletal maturation.Calcif. Tissue Int.76326–335. 10.1007/s00223-004-0161-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  HanX.BoydP. J.ColganS.MadriJ. A.HaasT. L. (2003). Transcriptional up-regulation of endothelial cell matrix metalloproteinase-2 in response to extracellular cues involves GATA-2.J. Biol. Chem.27847785–47791. 10.1074/jbc.m309482200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  HarrisS. E.GuoD.HarrisM. A.KrishnaswamyA.LichtlerA. (2003). Transcriptional regulation of BMP-2 activated genes in osteoblasts using gene expression microarray analysis: role of Dlx2 and Dlx5 transcription factors.Front. Biosci.8:s1249–s1265.

  • Pubmed Abstract
  • Google Scholar

• 123

  HeinoT. J.HentunenT. A.VaananenH. K. (2002). Osteocytes inhibit osteoclastic bone resorption through transforming growth factor-beta: enhancement by estrogen.J. Cell. Biochem.85185–197. 10.1002/jcb.10109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  HienzS. A.PaliwalS.IvanovskiS. (2015). Mechanisms of bone resorption in periodontitis.J. Immunol. Res.2015:615486. 10.1155/2015/615486

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  HikitaA.YanaI.WakeyamaH.NakamuraM.KadonoY.OshimaY.et al (2006). Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappa B ligand.J. Biol. Chem.28136846–36855. 10.1074/jbc.m606656200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  HiraoM.HashimotoJ.YamasakiN.AndoW.TsuboiH.MyouiA.et al (2007). Oxygen tension is an important mediator of the transformation of osteoblasts to osteocytes.J. Bone Miner. Metab.25266–276. 10.1007/s00774-007-0765-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  HollidayL. S.WelgusH. G.FliszarC. J.VeithG. M.JeffreyJ. J.GluckS. L. (1997). Initiation of osteoclast bone resorption by interstitial collagenase.J. Biol. Chem.27222053–22058. 10.1074/jbc.272.35.22053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  HolmbeckK.BiancoP.CaterinaJ.YamadaS.KromerM.KuznetsovS. A.et al (1999). MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.Cell9981–92. 10.1016/s0092-8674(00)80064-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  HolmbeckK.BiancoP.ChrysovergisK.YamadaS.Birkedal-HansenH. J. (2003). MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth.Cell Biol.163661–671. 10.1083/jcb.200307061

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  HolmbeckK.BiancoP.PidouxI.InoueS.BillinghurstR. C.WuW.et al (2005). The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone.J. Cell Sci.118147–156. 10.1242/jcs.01581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  HolmbeckK.SzabovL. (2006). Aspects of extracellular matrix remodeling in development and disease.Birth Defects Res. C Embryo. Today7811–23. 10.1002/bdrc.20064

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  HoltI.DavieM. W.MarshallM. J. (1996). Osteoclasts are not the main source of interleukin-6 in mouse parietal bone.Bone18221–226. 10.1016/8756-3282(95)00482-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  HouP.TroenT.OvejeroM. C.KirkegaardT.AndersenT. L.ByrjalsenI.et al (2004). Matrix metalloproteinase-12 (MMP-12) in osteoclasts: new lesson on the involvement of MMPs in bone resorption.Bone3437–47. 10.1016/j.bone.2003.08.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  HuangW.LiW. Q.DehnadeF.ZafarullahM. (2002). Tissue inhibitor of metalloproteinases-4 (TIMP-4) gene expression is increased in human osteoarthritic femoral head cartilage.J. Cell. Biochem.85295–303. 10.1002/jcb.10138

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  HuangW.YangS.ShaoJ.LiY. P. (2007). Signaling and transcriptional regulation in osteoblast commitment and differentiation.Front. Biosci.12:3068–3092.

  • Google Scholar

• 136

  HughesD. E.SalterD. M.SimpsonR. (1994). CD44 expression in human bone: a novel marker of osteocytic differentiation.J. Bone Miner. Res.939–44. 10.1002/jbmr.5650090106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  IkedaS.MorishitaY.TsutsumiH.ItoM.ShiraishiA.AritaS.et al (2003). Reductions in bone turnover, mineral, and structure associated with mechanical properties of lumbar vertebra and femur in glucocorticoid-treated growing minipigs.Bone33779–787. 10.1016/s8756-3282(03)00263-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  InadaM.WangY.ByrneM. H.MiyauraC.KraneS. M. (2001). Mice with null mutation in collagenase-3 (Matrix Metalloproteinase [MMP]-13) exhibit altered bone remodeling and increased bone mass.J. Bone Miner. Res.16:S149.

  • Google Scholar

• 139

  InadaM.WangY.ByrneM. H.MiyauraC.KraneS. M. (2002). Loss of function of matrix metalloproteinase-13 (MMP-13) affects collagen accumulation and bone formation.J. Bone Miner. Res.16:S171.

  • Google Scholar

• 140

  InadaM.WangY.ByrneM. H.RahmanM. U.MiyauraC.Lopez-OtinC.et al (2004). Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification.Proc. Natl. Acad. Sci. U.S.A.10117192–17197. 10.1073/pnas.0407788101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  InoueK.Mikuni-TakagakiY.OikawaK.ItohT.InadaM.NoguchiT.et al (2006). A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism.J. Biol. Chem.28133814–33824. 10.1074/jbc.m607290200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  IshidaN.HayashiK.HoshijimaM.OgawaT.KogaS.MiyatakeY.et al (2002). Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator.J. Biol. Chem.27741147–41156. 10.1074/jbc.m205063200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  IshikawaT.NishigakiF.MiyataS.HirayamaY.MinouraK.ImanishiJ.et al (2005). Prevention of progressive joint destruction in collagen-induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031.Br. J. Pharmacol.144133–143. 10.1038/sj.bjp.0706054

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  ItoA.MukaiyamaA.ItohY.NagaseH.ThogersenI. B.EnghildJ. J.et al (1996). Degradation of interleukin 1 beta by matrix metalloproteinases.J. Biol. Chem.27114657–14660.

  • Pubmed Abstract
  • Google Scholar

• 145

  IyerR. P.PattersonN. L.FieldsG. B.LindseyM. L. (2012). The history of matrix metalloproteinases: milestones, myths, and misperceptions.Am. J. Physiol. Heart Circ. Physiol.303H919–H930. 10.1152/ajpheart.00577.2012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  JacksonM. T.MoradiB.SmithM. M.JacksonC. J.LittleC. B. (2014). Activation of matrix metalloproteinases 2, 9, and 13 by activated protein C in human osteoarthritic cartilage chondrocytes.Arthritis Rheumatol.661525–1536. 10.1002/art.38401

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  JavaheriB.HopkinsonM.PouletB.PollardA. S.ShefelbineS. J.ChangY. M.et al (2016). Deficiency and also transgenic overexpression of TIMP-3 both lead to compromised bone mass and architecture in vivo.PLoS One11:e0159657. 10.1371/journal.pone.0159657

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  JiangY. B.ZhaoJ.GenantH. K.DequekerJ.GeusensP. (1997). Long-term changes in bone mineral and biomechanical properties of vertebrae and femur in aging, dietary calcium restricted and/or estrogen-deprived/-replaced rats.J. Bone Miner. Res.12820–831. 10.1359/jbmr.1997.12.5.820

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  JimenezM. J.BalbinM.LopezJ. M.AlvarezJ.KomoriT.Lopez-OtınC. (1999). Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation.Mol. Cell. Biol.194431–4442. 10.1128/mcb.19.6.4431

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  JingR.LiuY.GuoP.NiT.GaoX.MeiR.et al (2018). Evaluation of common variants in matrix metalloproteinase-9 gene with lumbar disc herniation in han chinese population.Genet. Test Mol. Biomarkers22622–629. 10.1089/gtmb.2018.0080

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  JohanssonN.Saarialho-KereU.AirolaK.HervaR.NissinenL.WestermarckJ.et al (1997). Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development.Dev. Dyn.208387–397. 10.1002/(sici)1097-0177(199703)208:3<387::aid-aja9>3.0.co;2-e

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  KajitaM.ItohY.ChibaT.MoriH.OkadaA.KinohH.et al (2001). Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration.J. Cell Biol.153893–904. 10.1083/jcb.153.5.893

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  KamiokaH.HonjoT.Takano-YamamotoT. (2001). A three-dimensional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy.Bone28145–149. 10.1016/s8756-3282(00)00421-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  KamiyaN.YeL.KobayashiT.MochidaY.YamauchiM.KronenbergH. M.et al (2008). BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway.Development1353801–3811. 10.1242/dev.025825

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  KapurS.BaylinkD. J.LauK. H. (2003). Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways.Bone32241–251. 10.1016/s8756-3282(02)00979-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  KarsdalM. A.AndersenT. A.BonewaldL.ChristiansenC. (2004). Matrix metalloproteinases (MMPs) safeguard osteoblasts from apoptosis during transdifferentiation into osteocytes: MT1-MMP maintains osteocyte viability.DNA Cell Biol.23155–165. 10.1089/104454904322964751

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  KarsdalM. A.FjordingM. S.FogedN. T.DelaisseJ. M.LochterA. (2001). Transforming growth factor-β-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogen-activated protein kinase- and matrix metalloproteinase-dependent pathway.J. Biol. Chem.27639350–39358. 10.1074/jbc.m008738200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  KarsdalM. A.HenriksenK.LeemingD. J.WoodworthT.VassiliadisE.Bay-JensenA. C. (2010). Novel combinations of Post-Translational Modification (PTM) neo-epitopes provide tissue-specific biochemical markers–are they the cause or the consequence of the disease?Clin. Biochem.43793–804. 10.1016/j.clinbiochem.2010.03.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  KarsdalM. A.LarsenL.EngsigM. T.LouH.FerrerasM.LochterA.et al (2002). Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis.J. Biol. Chem.27744061–44067. 10.1074/jbc.m207205200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  KarsdalM. A.WoodworthT.HenriksenK.MaksymowychW. P.GenantH.VergnaudP.et al (2011). Biochemical markers of ongoing joint damage in rheumatoid arthritis - current and future applications, limitations and opportunities.Arthritis Res. Ther.13:215. 10.1186/ar3280

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  KasperG.GlaeserJ. D.GeisslerS.OdeA.TuischerJ.MatziolisG.et al (2007). Matrix metalloprotease activity is an essential link between mechanical stimulus and mesenchymal stem cell behavior.Stem Cells251985–1994. 10.1634/stemcells.2006-0676

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  KawaguchiH.PilbeamC. C.RaiszL. G. (1994). Anabolic effects of 3,3’,5-triiodothyronine and triiodothyroacetic acid in cultured neonatal mouse parietal bones.Endocrinology135971–976. 10.1210/endo.135.3.7520864

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  KawaguchiH.PilbeanC. C.HarrisonJ. R.RaiszL. G. (1995). The role of prostaglandins in the regulation of bone metabolism.Clin. Orthop.31336–46.

  • Pubmed Abstract
  • Google Scholar

• 164

  KennedyA. M.InadaM.KraneS. M.ChristieP. T.HardingB.Lopez-OtinC.et al (2005). MMP13 mutation causes spondyloepimetaphyseal dysplasia. Missouri type (SEMDMO).J. Clin. Invest.1152832–2842. 10.1172/jci22900

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  Kerschan-SchindlK.EbenbichlerG. (2012). “Osteoimmunological aspects of biomechanics,” in Principles of Osteoimmunology, Molecular Mechanisms and Clinical Applications, ed.PietschmannP., (New York, NY: SpringerWienNewYork), 97–107.

  • Google Scholar

• 166

  KimH. J.ZhaoH.KitauraH.BhattacharyyaS.BrewerJ. A.MugliaL. J.et al (2006). Glucocorticoids suppress bone formation via the osteoclast.J. Clin. Invest.1162152–2160. 10.1172/jci28084

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  KimJ. W.SimmerJ. P.HartT. C.HartP. S.RamaswamiM. D.BartlettJ. D.et al (2005). MP-20 mutation in autosomal recessive pigmented hypomaturation amelogenesis imperfecta.J. Med. Genet.42271–275. 10.1136/jmg.2004.024505

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  KimM. H.ParkM.BaekS. H.KimH. J.KimS. H. (2011). Molecules and signaling pathways involved in the expression of OC-STAMP during osteoclastogenesis.Amino Acids401447–1459. 10.1007/s00726-010-0755-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  KimY.SatoK.AsagiriM.MoritaI.SomaK.TakayanagiH. (2005). Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis.J. Biol. Chem.28032905–32913. 10.1074/jbc.m505820200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  KiniU.NandeeshB. N. (2012). “Physiology of bone formation, remodeling, and metabolism,” in Radionuclide and Hybrid Bone Imaging, edsFogelmanI.GnanasegaranG.Van der WallH., (Berlin: Springer-Verlag), 29–57. 10.1007/978-3-642-02400-9_2

  • CrossRef
  • Google Scholar

• 171

  KleinT.BischoffR. (2011). Physiology and pathophysiology of matrix metalloproteases.Amino Acids41271–290. 10.1007/s00726-010-0689-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  Knothe-TateM. L.AdamsonJ. R.TamiA. E.BauerT. W. (2004). The osteocyte.Int. J. Biochem. Cell Biol.361–8.

  • Pubmed Abstract
  • Google Scholar

• 173

  KogaT.InuiM.InoueK.KimS.SuematsuA.KobayashiE.et al (2004). Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.Nature428758–763. 10.1038/nature02444

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  KogaT.MatsuiY.AsagiriM.KodamaT.de CrombruggheB.NakashimaK.et al (2005). NFAT and Osterix cooperatively regulate bone formation.Nat. Med.11880–885. 10.1038/nm1270

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  KojimaT.HasegawaT.de FreitasP. H.YamamotoT.SasakiM.HoriuchiK.et al (2013). Histochemical aspects of the vascular invasion at the erosion zone of the epiphyseal cartilage in MMP-9-deficient mice.Biomed. Res.34119–128. 10.2220/biomedres.34.119

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  KoolwijkP.SideniusN.PetersE.SierC. F.HanemaaijerR.BlasiF.et al (2001). Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices.Blood973123–3131. 10.1182/blood.v97.10.3123

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  KosakiN.TakaishiH.KamekuraS.KimuraT.OkadaY.MinqiL.et al (2007). Impaired bone fracture healing in matrix metalloproteinase-13 deficient mice.Biochem. Biophys. Res. Commun.354846–851. 10.1016/j.bbrc.2006.12.234

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  KoskinenA.VuolteenahoK.NieminenR.MoilanenT.MoilanenE. (2011). Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients.Clin. Exp. Rheumatol.2957–64.

  • Pubmed Abstract
  • Google Scholar

• 179

  KotakeS.UdagawaN.TakahashiN.MatsuzakiK.ItohK.IshiyamaS.et al (1999). IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.J. Clin. Invest.1031345–1352. 10.1172/jci5703

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  KraneS. M.InadaM. (2008). Matrix metalloproteinases and bone.Bone437–18. 10.1016/j.bone.2008.03.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  KrishnanV.BryantH. U.MacdougaldO. A. (2006). Regulation of bone mass by Wnt signaling.J. Clin. Invest.1161202–1209. 10.1172/jci28551

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  KusanoK.MiyauraC.InadaM.TamuraT.ItoA.NagaseH.et al (1998). Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption.Endocrinology1391338–1345. 10.1210/endo.139.3.5818

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  LaceyD. L.TimmsE.TanH. L.KelleyM. J.DunstanC. R.BurgessT.et al (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.Cell93165–176. 10.1016/s0092-8674(00)81569-x

  • CrossRef
  • Google Scholar

• 184

  LafleurM. A.MercuriF. A.RuangpanitN.SeikiM.SatoH.ThompsonE. W. (2006). Type I collagen abrogates the clathrin-mediated internalization of membrane type 1 matrix metalloproteinase (MT1-MMP) via the MT1-MMP hemopexin domain.J. Biol. Chem.2816826–6840. 10.1074/jbc.m513084200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  LamJ.TakeshitaS.BarkerJ. E.KanagawaO.RossF. P.TeitelbaumS. L. (2000). TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.J. Clin. Invest.1061481–1488. 10.1172/jci11176

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  LanskeB.AmlingM.NeffL.GuiducciJ.BaronR.KronenbergH. M. (1999). Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development.J. Clin. Invest.104399–407. 10.1172/jci6629

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  LassenN. E.AndersenT. L.PløenG. G.SøeK.HaugeE. M.HarvingS.et al (2017). Coupling of bone resorption and formation in real time: new knowledge gained from human haversian BMUs.J. Bone Miner. Res.321395–1405. 10.1002/jbmr.3091

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  LazarusS.TsengH. W.LawrenceF.WoodruffM. A.DuncanE. L.PettitA. R. (2017). Characterization of normal murine carpal bone development prompts re-evaluation of pathologic osteolysis as the cause of human carpal-tarsal osteolysis disorders.Am. J. Pathol.1871923–1934. 10.1016/j.ajpath.2017.05.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  LeeH.OverallC. M.McCullochC. A.SodekJ. (2006). A critical role for the membrane-type 1 matrix metalloproteinase in collagen phagocytosis.Mol. Biol. Cell.174812–4826. 10.1091/mbc.e06-06-0486

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  LiG.LiuD.ZhangY.QianY.ZhangH.GuoS.et al (2013). Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-κB-mediated matrix metalloproteinase-9 expression.PLoS One8:e008905. 10.1371/journal.pone.0068905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  LiN. G.ShiZ. H.TangY. P.WangZ. J.SongS. L.QianL. H.et al (2011). New hope for the treatment of osteoarthritis through selective inhibition of MMP-13.Curr. Med. Chem.18977–1001. 10.2174/092986711794940905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  LiP. B.TangW. J.WangK.ZouK.CheB. (2017). Expressions of IL-1α and MMP-9 in degenerated lumbar disc tissues and their clinical significance.Eur. Rev. Med. Pharmacol. Sci.214007–4013.

  • Google Scholar

• 193

  LiY. P.ChenW.LiangY.LiE.StashenkoP. (1999). Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification.Nat. Genet.23447–451. 10.1038/70563

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  LiangH. P. H.XuJ.XueM.JacksonC. J. (2016). Matrix metalloproteinases in bone development and pathology: current knowledge and potential clinical utility.Metalloproteinases Med.393–102. 10.2147/mnm.s92187

  • CrossRef
  • Google Scholar

• 195

  LiaoE. Y.LiaoH. J.GuoL. J.ZhouH. D.WuX. P.DaiR. C.et al (2004). Membrane-type matrix metalloproteinase-1 (MT1-MMP) is down-regulated in estrogen-deficient rat osteoblast in vivo.J. Endocrinol. Invest.271–5. 10.1007/bf03350902

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  LieuS.HansenE.DediniR.BehonickD.WerbZ.MiclauT.et al (2011). Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2.Dis. Model Mech.4203–211. 10.1242/dmm.006304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  LindseyM. L.ZoueinF. A.TianY.IyerR. P.De Castro BrasL. E. (2015). Osteopontin is proteolytically processed by matrix metalloproteinase 9.Can. J. Physiol. Pharmacol.293879–886. 10.1139/cjpp-2015-0019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  LiuJ.KhalilR. A. (2017). Matrix metalloproteinase inhibitors as investigational and therapeutic tools in unrestrained tissue remodeling and pathological disorders.Prog. Mol. Biol. Transl. Sci.148355–420. 10.1016/bs.pmbts.2017.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  LiuS.TangW.FangJ.RenJ.LiH.XiaoZ.et al (2009). Novel regulators of Fgf23 expression and mineralization in Hyp bone.Mol. Endocrinol.231505–1518. 10.1210/me.2009-0085

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  LiuS.ZhouJ.TangW.JiangX.RoweD. W.QuarlesD. L. (2006). Pathogenic role of Fgf23 in Hyp mice.Am. J. Physiol. Endocrinol. Metab.291E38–E49. 10.1210/me.2009-0085

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  LiuY. H.TangZ.KunduR. K.WuL.LuoW.ZhuD.et al (1999). Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans.Dev. Biol.205260–274. 10.1006/dbio.1998.9114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  LoffekS.SchillingO.FranzkeC. W. (2011). Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance.Eur. Respir. J.38191–208. 10.1183/09031936.00146510

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  LoganC. Y.NusseR. (2004). The Wnt signaling pathway in development and disease.Annu. Rev. Cell Dev. Biol.20781–810.

  • Pubmed Abstract
  • Google Scholar

• 204

  Lopez-OtinC.PalavalliL. H.SamuelsY. (2009). Protective roles of matrix metalloproteinases: from mouse models to human cancer.Cell Cycle83657–3662. 10.4161/cc.8.22.9956

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  LovibondA. C.HaqueS. J.ChambersT. J.FoxS. W. (2003). TGF-beta-induced SOCS3 expression augments TNF-alpha-induced osteoclast formation.Biochem. Biophys. Res. Commun.309762–767. 10.1016/j.bbrc.2003.08.068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  LozitoT. P.JacksonW. M.NestiL. J.TuanR. S. (2014). Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs.Matrix Biol.34132–143. 10.1016/j.matbio.2013.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  LozitoT. P.TuanR. S. (2011). Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs.J. Cell Physiol.226385–396. 10.1002/jcp.22344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  LuC.LiX. Y.HuY.RoweR. G.WeissS. J. (2010). MT1-MMP controls human mesenchymal stem cell trafficking and differentiation.Blood115221–229. 10.1182/blood-2009-06-228494

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  LuP.TakaiK.WeaverV. M.WerbZ. (2011). Extracellular matrix degradation and remodeling in development and disease.Cold Spring Harb. Perspect. Biol.3:a005058. 10.1101/cshperspect.a005058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  LuanZ.ChaseA. J.NewbyA. C. (2003). Statins inhibit secretion of metalloproteinases-1, -2, -3, and -9 from vascular smooth muscle cells and macrophages.Arterioscler. Thromb. Vasc. Biol.23769–775. 10.1161/01.atv.0000068646.76823.ae

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  LuoJ.YangZ.MaY.YueZ.LinH.QuG.et al (2016). LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption.Nat. Med.22539–546. 10.1038/nm.4076

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  LvC.YangS.ChenX.ZhuX.LinW.WangL.et al (2017). MicroRNA-21 promotes bone mesenchymal stem cells migration in vitro by activating PI3K/Akt/MMPs pathway.J. Clin. Neurosci.46156–162. 10.1016/j.jocn.2017.07.040

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  LynchC. C. (2011). Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis.Bone4844–53. 10.1016/j.bone.2010.06.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  LynchC. C.HikosakaA.AcuffH. B.MartinM. D.KawaiN.SinghR. K.et al (2005). MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL.Cancer Cell7485–496. 10.1016/j.ccr.2005.04.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  MacDonaldB. R. (1986). Parathyroid hormone, prostaglandins and bone resorption.World Rev. Nutr. Diet47163–201. 10.1159/000412334

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  MadsenD. H.JürgensenH. J.IngvarsenS.MelanderM. C.AlbrechtsenR.HaldA.et al (2013). Differential actions of the endocytic collagen receptor uPARAP/Endo180 and the collagenase MMP-2 in bone homeostasis.PLoS One8:e71261. 10.1371/journal.pone.0071261

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  MaedaY.NakamuraE.NguyenM. T.SuvaL. J.SwainF. L.RazzaqueM. S.et al (2007). Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone.Proc. Natl. Acad. Sci. U.S.A.1046382–6387. 10.1073/pnas.0608449104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  MaffioliP.DerosaG. (2015). “Overview of biochemical markers of bone metabolism,” in Bone Disease, Biomarkers in Disease: Methods, Discoveries and Applications, ed.PreedyV. R., (Dordrecht: Springer Science+Business Media), 1–19. 10.1007/978-94-007-7745-3_24-1

  • CrossRef
  • Google Scholar

• 219

  MahlC.EgeaV.MegensR. T. A.PitschT.SantovitoD.WeberC.et al (2016). RECK (reversion-inducing cysteine-rich protein with Kazal motifs) regulates migration, differentiation and Wnt/β-catenin signaling in human mesenchymal stem cells.Cell Mol. Life Sci.731489–1501. 10.1007/s00018-015-2054-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  MalaponteG.HafsiS.PoleselJ.CastellanoG.SpessottoP.GuarneriC.et al (2016). Tumor microenvironment in diffuse large B-cell lymphoma: matrix metalloproteinases activation is mediated by osteopontin overexpression.Biochim. Biophys. Acta1863483–489. 10.1016/j.bbamcr.2015.09.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  ManciniA.di BattistaJ. A. (2006). Transcriptional regulation of matrix metalloprotease gene expression in health and disease.Front. Biosci.11:423–446.

  • Pubmed Abstract
  • Google Scholar

• 222

  ManducaP.CastagninoA.LombardiniD.MarchisioS.SoldanoS.UliviV.et al (2009). Role of MT1-MMP in the osteogenic differentiation.Bone44251–265. 10.1016/j.bone.2008.10.046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  MannelloF.TontiG.PapaS. (2005). Matrix metalloproteinase inhibitors as anticancer therapeutics.Curr. Cancer Drug Targets5285–298. 10.2174/1568009054064615

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  ManolagasS. C. (2000). Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.Endocr. Rev.21115–137. 10.1210/edrv.21.2.0395

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  MarieP. J. (2003). Fibroblast growth factor signaling controlling osteoblast differentiation.Gene31623–32. 10.1016/s0378-1119(03)00748-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  MartignettiJ. A.AqeelA. A.SewairiW. A.BoumahC. E.KambourisM.MayoufS. A.et al (2001). Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.Nat. Genet.28261–265. 10.1038/90100

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  MassovaI.KotraL. P.FridmanR.MobasheryS. (1998). Matrix metalloproteinases: structures, evolution, and diversification.FASEB J.121075–1095. 10.1096/fasebj.12.12.1075

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  MatsuguchiT.ChibaN.BandowK.KakimotoK.MasudaA.OhnishiT. (2009). JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation.J. Bone Miner. Res.24398–410. 10.1359/jbmr.081107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  MatsumotoM.KogawaM.WadaS.TakayanagiH.TsujimotoM.KatayamaS.et al (2004). Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1.J. Biol. Chem.27945969–45979. 10.1074/jbc.m408795200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  MatsuoK.GalsonD. L.ZhaoC.PengL.LaplaceC.WangK. Z.et al (2004). Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos.J. Biol. Chem.27926475–26480. 10.1074/jbc.m313973200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  MattotV.RaesM. B.HenrietP.EeckhoutY.StehelinD.VandenbunderB.et al (1995). Expression of interstitial collagenase is restricted to skeletal tissue during mouse embryogenesis.J. Cell Sci.108529–535.

  • Pubmed Abstract
  • Google Scholar

• 232

  MattssonJ. P.SchlesingerP. H.KeelingD. J.TeitelbaumS. L.StoneD. K.XieX. S. (1994). Isolation and reconstitution of a vacuolar-type proton pump of osteoclast membranes.J. Biol. Chem.26924979–24982.

  • Pubmed Abstract
  • Google Scholar

• 233

  MauramoM.RamseierA. M.MauramoE.BuserA.TervahartialaT.SorsaT.et al (2018). Associations of oral fluid MMP-8 with periodontitis in Swiss adult subjects.Oral Dis.24449–455. 10.1111/odi.12769

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  McGowanP. M.DuffyM. J. (2008). Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database.Ann. Oncol.191566–1572. 10.1093/annonc/mdn180

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  MeikleM. C.BordS.HembryR. M.CompstonJ.CroucherP. I.ReynoldsJ. J. (1992). Human osteoblasts in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines.J. Cell Sci.1031093–1099.

  • Pubmed Abstract
  • Google Scholar

• 236

  MengF.YangH.AithaM.GeorgeS.TierneyD. L.CrowderM. W. (2016). Biochemical and spectroscopic characterization of the catalytic domain of MMP16 (cdMMP16).J. Biol. Inorg. Chem.21523–535. 10.1007/s00775-016-1362-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  MessaritouG.EastL.RoghiC.IsackeC. M.YarwoodH. (2009). Membrane type-1 matrix metalloproteinase activity is regulated by the endocytic collagen receptor Endo180.J. Cell Sci.1224042–4048. 10.1242/jcs.044305

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  Mikuni-TakagakiY. (1999). Mechanical responses and signal transduction pathways in stretched osteocytes.J. Bone Miner. Metab.1757–60. 10.1007/s007740050065

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  MillerB.SpevakL.LukashovaL.JavaheriB.PitsillidesA. A.BoskeyA.et al (2017). Altered bone mechanics, architecture and composition in the skeleton of TIMP-3-deficient mice.Calcif. Tissue Int.100631–640. 10.1007/s00223-017-0248-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  MillsB. G.FraustoA. (1997). Cytokines expressed in multinucleated cells: Paget’s disease and giant cell tumors versus normal bone.Calcif. Tissue Int.6116–21. 10.1007/s002239900285

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  MimuraH.CaoX.RossF. P.ChibaM.TeitelbaumS. L. (1994). 1,25-Dihydroxyvitamin D3 transcriptionally activates the beta 3-integrin subunit gene in avian osteoclast precursors.Endocrinology1341061–1066. 10.1210/endo.134.3.8119143

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  MittalR.PatelA. P.DebsL. H.NguyenD.PatelK.GratiM.et al (2016). Intricate functions of matrix metalloproteinases in physiological and pathological conditions.J. Cell Physiol.2312599–2621. 10.1002/jcp.25430

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  MiyamotoT. (2006). The dendritic cell-specific transmembrane protein DC-STAMP is essential for osteoclast fusion and osteoclast bone-resorbing activity.Mod. Rheumatol.16341–342. 10.3109/s10165-006-0524-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  MiyauchiA.AlvarezJ.GreenfieldE. M.TetiA.GranoM.ColucciS.et al (1991). Recognition of osteopontin and related peptides by an alpha v beta 3 integrin stimulates immediate cell signals in osteoclasts.J. Biol. Chem.26620369–20374.

  • Pubmed Abstract
  • Google Scholar

• 245

  MiyauchiA.GotohM.KamiokaH.NotoyaK.SekiyaH.TakagiY.et al (2006). AlphaVbeta3 integrin ligands enhance volume-sensitive calcium influx in mechanically stretched osteocytes.J Bone Miner. Metab.24498–504. 10.1007/s00774-006-0716-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  MiyauchiA.NotoyaK.Mikuni-TakagakiY.TakagiY.GotoM.MikiY.et al (2000). Parathyroid hormone-activated volume-sensitive calcium influx pathways in mechanically located osteocytes.J. Biol. Chem.2753335–3342. 10.1074/jbc.275.5.3335

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  MocsaiA.HumphreyM. B.Van ZiffleJ. A.HuY.BurghardtA.SpustaS. C.et al (2004). The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase.Proc. Natl. Acad. Sci. U.S.A.1016158–6163. 10.1073/pnas.0401602101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  MohanakrishnanV.BalasubramanianA.MahalingamG.PartridgeN. C.RamachandranI.SelvamuruganN. (2018). Parathyroid hormone-induced down-regulation of miR-532-5p for matrix metalloproteinase-13 expression in rat osteoblasts.J. Cell Biochem.1196181–6193. 10.1002/jcb.26827

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  MosekildeL.DanielsenD. D.KnudsenU. B. (1993). The effect of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats.Bone141–6. 10.1016/8756-3282(93)90248-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  MosigR. A.DowlingO.DiFeoA.RamirezM. C.ParkerI. C.AbeE.et al (2007). Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth.Hum. Mol. Genet.161113–1123. 10.1093/hmg/ddm060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  MottJ. D.ThomasC. L.RosenbachM. T.TakaharaK.GreenspanD. S.BandaM. J. (2000). Post-translational proteolytic processing of procollagen C-terminal proteinase enhancer releases a metalloproteinase inhibitor.J. Biol. Chem.2751384–1390. 10.1074/jbc.275.2.1384

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  MundyG. (1993). Cytokines and growth factors in the regulation of bone remodeling.J. Bone Miner. Res.8S505–S510.

  • Pubmed Abstract
  • Google Scholar

• 253

  MurrayE. J. B.TramK. K.-T.SpencerM. J.TidballJ. G.MurrayS. S.LeeD. B. N. (1995). PTH mediated osteoblast retraction: possible participation of the calpain pathway.Miner. Electrolyte Metab.21184–188.

  • Pubmed Abstract
  • Google Scholar

• 254

  NagaseH.VisseR.MurphyG. (2006). Structure and function of matrix metalloproteinases and TIMPs.Cardiovasc. Res.69562–573. 10.1016/j.cardiores.2005.12.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  NakashimaA.TamuraM. (2006). Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation.Front. Biosci.11:1667–1678.

  • Pubmed Abstract
  • Google Scholar

• 256

  NannuruK. C.FutakuchiM.VarneyM. L.VincentT. M.MarcussonE. G.SinghR. K. (2010). Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-beta signaling at the tumor-bone interface.Cancer Res.703494–3504. 10.1158/0008-5472.CAN-09-3251

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  NashT. J.HowlettC. R.MartinC.SteeleJ.JohnsonK. A.HicklinD. J. (1994). Effects of platelet-derived growth factor on tibial osteotomies in rabbits.Bone15203–208. 10.1016/8756-3282(94)90709-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  NeuholdL. A.KillarL.ZhaoW.SungM. L.WarnerL.KulikJ.et al (2001). Postnatal expression in hyaline cartilage of constitutively active human collagenase-13 (MMP-13) induces osteoarthritis in mice.J. Clin. Investig.10735–44. 10.1172/jci10564

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  NguyenM.ArkellJ.JacksonC. J. (2000). Activated protein C directly activates human endothelial gelatinase A.J. Biol. Chem.2759095–9098. 10.1074/jbc.275.13.9095

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  NymanJ. S.LynchC. C.PerrienD. S.ThiolloyS.O’QuinnE. C.PatilC. A.et al (2011). Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue-level properties of bone.J. Bone. Miner. Res.261252–1260. 10.1002/jbmr.326

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  OhJ.TakahashiR.AdachiE.KondoS.KuratomiS.NomaA.et al (2004). Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice.Oncogene235041–5048. 10.1038/sj.onc.1207688

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  OhJ.TakahashiR.KondoS.MizoguchiA.AdachiE.SasaharaR. M.et al (2001). The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.Cell107789–800. 10.1016/s0092-8674(01)00597-9

  • CrossRef
  • Google Scholar

• 263

  OkadaM.ShinmeiY.TanakaO.NakaK.KimuraA.NakanishiI.et al (1992). Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium.Lab. Invest.66680–690.

  • Pubmed Abstract
  • Google Scholar

• 264

  OrtegaN.BehonickD.DominiqueS.WerbZ. (2003). How proteases regulate bone morphogenesis.Ann. N. Y. Acad. Sci.995109–116. 10.1111/j.1749-6632.2003.tb03214.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  OrtegaN.BehonickD. J.ColnotC.CooperD. N.WerbZ. (2005). Galectin-3 is a downstream regulator of matrix metalloproteinase-9 function during endochondral bone formation.Mol. Biol. Cell163028–3039. 10.1091/mbc.e04-12-1119

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  OrtegaN.WangK.FerraraN.WerbZ.VuT. H. (2010). Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation.Dis. Model Mech.3224–235. 10.1242/dmm.004226

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  OverallC. M.WranaJ. L.SodekJ. (1991). Transcriptional and posttranscriptional regulation of 72-kDa gelatinase type-IV collagenase by transforming growth factor-beta-1 in human fibroblasts: comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene-expression.J. Biol. Chem.26614064–14071.

  • Google Scholar

• 268

  OzdemirD.HartP. S.RyulO. H.ChoiS. J.Ozdemir-KaratasM.FiratliE.et al (2005). MMP20 active-site mutation in hypomaturation amelogenesis imperfecta.J. Dent. Res.841031–1035. 10.1177/154405910508401112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  Page-McCawA.EwaldA. J.WerbZ. (2007). Matrix metalloproteinases and the regulation of tissue remodeling.Nat. Rev. Mol. Cell Biol.8221–233.

  • Google Scholar

• 270

  PaivaK. B. S.GranjeiroJ. M. (2014). Bone tissue remodeling and development: focus on matrix metalloproteinase functions.Arch. Biochem. Biophys.56174–87. 10.1016/j.abb.2014.07.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  PaivaK. B. S.GranjeiroJ. M. (2017). Matrix metalloproteinases in bone resorption, remodeling, and repair.Prog. Mol. Biol. Transl. Sci.148203–303. 10.1016/bs.pmbts.2017.05.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  PapT.Korb-PapA. (2015). Cartilage damage in osteoarthritis and rheumatoid arthritis-two unequal siblings.Nat. Rev. Rheumatol.11606–615. 10.1038/nrrheum.2015.95

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  PapT.ShigeyamaY.KuchenS.FernihoughJ. K.SimmenB.GayR. E.et al (2000). Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis.Arthritis Rheum.431226–1232. 10.1002/1529-0131(200006)43:6<1226::aid-anr5>3.0.co;2-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  PapathanasiouI.MalizosK. N.TsezouA. (2012). Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes.Arthritis Res. Ther.14:R82. 10.1186/ar3805

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  Parra-TorresA. Y.Valdés-FloresM.OrozcoL.Velázquez-CruzR. (2013). “Molecular aspects of bone remodeling,” in Topics in Osteoporosis, ed.FloresM. V., (London: IntechOpen).

  • Google Scholar

• 276

  PegoE. R.FernandezI.NuñezM. J. (2018). Molecular basis of the effect of MMP-9 on the prostate bone metastasis: a review.Urol. Oncol.36272–282. 10.1016/j.urolonc.2018.03.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  PeiD.KangT.QiH. (2000). Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation.J. Biol. Chem.27533988–33997. 10.1074/jbc.m006493200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  PeiD.WeissS. J. (1995). Furin-dependent intracellular activation of the human stromelysin-3 zymogen.Nature375244–247. 10.1038/375244a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  PettitA. R.ChangM. K.HumeD. A.RaggattL. G. (2008). Osteal macrophages: a new twist on coupling during bone dynamics.Bone43976–982. 10.1016/j.bone.2008.08.128

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  PiccardH.Van den SteenP. E.OpdenakkerG. (2007). Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins.J. Leukoc. Biol.81870–892. 10.1189/jlb.1006629

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  PirapaharanD. C.OlesenJ. B.AndersenT. L.ChristensenS. B.Kjærsgaard-AndersenP.DelaisseJ. M.et al (2019). Catabolic activity of osteoblast lineage cells contributes to osteoclastic bone resorption in vitro.J. Cell Sci.15132. 10.1242/jcs.229351

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  PivettaE.ScapolanM.PecoloM.WassermannB.Abu-RumeilehI.BalestreriL.et al (2011). MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases.Breast Cancer Res.13:R105. 10.1186/bcr3047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 283

  PlotkinL. I.BruzzanitiA. (2019). Molecular signaling in bone cells: regulation of cell differentiation and survival.Adv. Protein Chem. Struc. Biol.116237–281. 10.1016/bs.apcsb.2019.01.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  PlotkinL. I.LezcanoV.ThostensonJ.WeinsteinR. S.ManolagasS. C.BellidoT. (2008). Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo.J. Bone Miner. Res.231712–1721. 10.1359/jbmr.080617

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  PlotkinL. I.ManolagasS. C.BellidoT. (2002). Transduction of cell survival signals by connexin-43 hemichannels.J. Biol. Chem.2778648–8657. 10.1074/jbc.m108625200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  PlotkinL. I.MathovI.AguirreJ. I.ParfittA. M.MangolasS. C.BellidoT. (2005). Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs.Am. J. Physiol. Cell Physiol.289C633–C643.

  • Pubmed Abstract
  • Google Scholar

• 287

  PooleK. E.van BezooijenR. L.LoveridgeN.HamersmaH.PapapoulosS. E.LowikC. W.et al (2005). Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation.FASEB J.191842–1844. 10.1096/fj.05-4221fje

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 288

  PorterS.ClarkI. M.KevorkianL.EdwardD. R. (2005). The ADAMTS metalloproteinases.Biochem. J.38615–27. 10.1042/bj20040424

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 289

  PulitiM.MomiS.FalcinelliE.GreseleP.BistoniF.TissiL. (2012). Contribution of matrix metalloproteinase 2 to joint destruction in group B Streptococcus-induced murine arthritis.Arthritis Rheum.641089–1097. 10.1002/art.33450

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 290

  QuinnJ. M. W.NealeS.FujikawaY.McGeeJ. D.AthanasouN. A. (1998). Human osteoclast formation from blood monocytes, peritoneal macrophages, and bone marrow cells.Calcif. Tissue Int.62527–531. 10.1007/s002239900473

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  QvistP.ChristiansenC.KarsdalM. A.MadsenS. H.SondergaardB. C.Bay-JensenA. C. (2010). Application of biochemical markers in development of drugs for treatment of osteoarthritis.Biomarkers151–19. 10.3109/13547500903295873

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  RagabA. A.NalepkaJ. L.BiY.GreenfieldE. M. (2002). Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells.Am. J. Physiol.283C679–C687.

  • Google Scholar

• 293

  RaiszL. G. (1993). Bone cell biology: new approaches and unanswered questions.J. Bone Miner. Res.8457–465.

  • Pubmed Abstract
  • Google Scholar

• 294

  RaiszL. G. (1997). The osteoporosis revolution.Ann. Intern. Med.126458–462.

  • Pubmed Abstract
  • Google Scholar

• 295

  RajaramS.MurawalaH.BuchP.PatelS.BalakrishnanS. (2016). Inhibition of BMP signaling reduces MMP-2 and MMP-9 expression and obstructs wound healing in regenerating fin of teleost fish Poecilia latipinna.Fish Physiol. Biochem.42787–794. 10.1007/s10695-015-0175-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 296

  RaunerM.SteinN.HofbauerL. C. (2012). “Basics of bone biology,” in Principles of Osteoimmunology, Molecular Mechanisms and Clinical Applications, ed.PietschmannP., (New York, NY: SpringerWienNewYork), 1–26. 10.1007/978-3-7091-0520-7_1

  • CrossRef
  • Google Scholar

• 297

  RawlinsonS. C.PitsillidesA. A.LanyonL. E. (1996). Involvement of different ion channels in osteoblasts’and osteocytes’ early responses to mechanical strain.Bone19609–614. 10.1016/s8756-3282(96)00260-8

  • CrossRef
  • Google Scholar

• 298

  RaynalC. P.DelmasD.ChenuC. (1996). Bone sialoprotein stimulates in vitro bone resorption.Endocrinology1372347–2354. 10.1210/endo.137.6.8641185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 299

  RoachH. I. (1994). Why does bone matrix contain non-collagenous proteins? The possible roles of osteocalcin, osteonectin, osteopontin and bone sialoprotein in bone mineralisation and resorption.Cell Biol. Int.18617–628. 10.1006/cbir.1994.1088

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 300

  RobeyP. G. (1989). The biochemistry of bone.Endocrinol. Metab. Clin. North Am.18858–902.

  • Google Scholar

• 301

  RoodmanG. D. (1999). Cell biology of the osteoclast.Exp. Hematol.271229–1241. 10.1016/s0301-472x(99)00061-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 302

  RoodmanG. D.KuriharaN.OhsakiY.KukitaA.HoskingD.DemulderA.et al (1992). Interleukin-6: a potential autocrine/paracrine agent in Paget’s disease of bone.J. Clin. Invest.8946–52. 10.1172/jci115584

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 303

  RoseB. J.KooymanD. L. (2016). A tale of two joints: the role of matrix metalloproteases in cartilage biology.Dis. Markers.20164895050. 10.1155/2016/4895050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 304

  RosenC. J.DonahueL. R. (1998). Insulin-like growth factors and bone-the osteoporosis connection revisited.Proc. Soc. Exp. Biol. Med.2191–7. 10.3181/00379727-219-44310

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 305

  RouzierC.VanatkaR.BannwarthS.PhilipN.CoussementA.Paquis-FlucklingerV.et al (2006). A novel homozygous MMP2 mutation in a family with Winchester syndrome.Clin. Genet.69271–276. 10.1111/j.1399-0004.2006.00584.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 306

  RoweP. S. N.KumagaiY.GutierrezG.GarrettI. R.BlacherR.RosenD.et al (2004). MEPE has the properties of an osteoblastic phosphatonin and minhibin.Bone34303–319. 10.1016/j.bone.2003.10.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 307

  RoweR. G.WeissS. (2009). Navigating ECM barriers at the invasive front: the cancer cell-stroma interface.Annu. Rev. Cell Dev. Biol.25567–595. 10.1146/annurev.cellbio.24.110707.175315

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 308

  RuanM.PedersonL.BradleyE. W.BambergerA. M.OurslerM. J. (2010). Transforming growth factor-{beta} coordinately induces suppressor of cytokine signaling 3 and leukemia inhibitory factor to suppress osteoclast apoptosis.Endocrinology1511713–1722. 10.1210/en.2009-0813

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 309

  RubinJ.RubinC.JacobsC. R. (2006). Molecular pathways mediating mechanical signalling in bone.Gene3671–16. 10.1016/j.gene.2005.10.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 310

  RuchonA. F.TenenhouseH. S.MarcinkiewiczM.SiegfriedG.AubinJ. E.DesGroseillersL.et al (2000). Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers.J. Bone Miner. Res.151440–1450. 10.1359/jbmr.2000.15.8.1440

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 311

  RutterJ. L.MitchellT. I.ButticeG.MeyersJ.GusellaJ. F.OzeliusL. J.et al (1998). A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription.Cancer Res.585321–5325.

  • Pubmed Abstract
  • Google Scholar

• 312

  SabbotaA. L.KimH. R.ZheX.FridmanR.BonfilR. D.CherM. L. (2010). Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration.Cancer Res705558–5566. 10.1158/0008-5472.CAN-09-4416

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 313

  SabehF.FoxD.WeissS. J. (2010). Membrane-type I matrix metalloproteinase-dependent regulation of rheumatoid arthritis synoviocyte function.J. Immunol.1846396–6406. 10.4049/jimmunol.0904068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 314

  SaftigP.HunzikerE.WehmeyerO.JonesS.BoydeA.RommerskirchW.et al (1998). Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice.Proc. Natl. Acad. Sci. U.S.A.9513453–13458. 10.1073/pnas.95.23.13453

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 315

  SageE. H.ReedM.FunkS. E.TruongT.SteadeleM.PuolakkainenP.et al (2003). Cleavage of the matricellular protein SPARC by matrix metalloproteinase 3 produces polypeptides that influence angiogenesis.J. Biol. Chem.27837849–37857. 10.1074/jbc.m302946200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 316

  SahebjamS.KhokhaR.MortJ. S. (2007). Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice.Arthritis Rheum.56905–909. 10.1002/art.22427

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 317

  SarkerH.HardyE.HaimourA.MaksymowychW. P.BottoL. D.Fernandez-PatronC. (2019). Identification of fibrinogen as a natural inhibitor of MMP-2.Sci. Rep.9:4340. 10.1038/s41598-019-40983-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 318

  SasakiT.GöhringW.MannK.MaurerP.HohenesterE.KnäuperV.et al (1997). Limited cleavage of extracellular matrix protein BM-40 by matrix metalloproteinases increases its affinity for collagens.J. Biol. Chem.2729237–9243. 10.1074/jbc.272.14.9237

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 319

  SatokataI.MaL.OhshimaH.BeiM.WooI.NishizawaK.et al (2000). Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation.Nat. Genet.24391–395. 10.1038/74231

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 320

  SawickiG. (2013). Intracellular regulation of matrix metalloproteinase-2 activity: new strategies in treatment and protection of heart subjected to oxidative stress.Scientifica2013:130451. 10.1155/2013/130451

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 321

  SchneiderG. B.KeyL. L.PopoffS. N. (1998). Osteopetrosis. Therapeutic strategies.Endocrinologist8409–417. 10.1097/00019616-199811000-00004

  • CrossRef
  • Google Scholar

• 322

  SemenovM.TamaiK.HeX. (2005). SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.J. Biol. Chem.28026770–26775. 10.1074/jbc.m504308200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 323

  ShahM.HuangD.BlickT.ConnorA.ReiterL. A.HardinkJ. R.et al (2012). An MMP13-selective inhibitor delays primary tumor growth and the onset of tumor-associated osteolytic lesions in experimental models of breast cancer.PLoS One7:e29615. 10.1371/journal.pone.0029615

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 324

  ShahnazariM.MartinB. R.LegetteL. L.LachcikP. J.WelchJ.WeaverC. M. (2009). Diet calcium levelbut not calcium supplement particle size affects bone density and mechanical properties in ovariectomized rats.J. Nutr.1391308–1314. 10.3945/jn.108.101071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 325

  ShenY.WinklerI. G.BarbierV.SimsN. A.HendyJ.LevesqueJ. P. (2010). Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo.PLoS One5:e13086. 10.1371/journal.pone.0013086

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 326

  SherL. B.WoitgeH. W.AdamsD. J.GronowiczG. A.KrozowskiZ.HarrisonJ. R.et al (2004). Transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2 in osteoblasts reveals an anabolic role for endogenous glucocorticoids in bone.Endocrinology145922–929. 10.1210/en.2003-0655

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 327

  ShiJ.SonM. Y.YamadaS.SzabovaL.KahanS.ChrysovergisK.et al (2008). Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis.Dev. Biol.313196–209. 10.1016/j.ydbio.2007.10.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 328

  ShoreE. M.XuM.FeldmanG. J.FenstermacherD. A.ChoT. J.ChoiI. H.et al (2006). A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.Nat. Genet.38525–527. 10.1038/ng1783

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 329

  SilverI. A.MurrillsR. J.EtheringtonD. J. (1988). Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts.Exp. Cell. Res.175266–276. 10.1016/0014-4827(88)90191-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 330

  SimsN. A.MartinT. J. (2014). Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit.Bonekey Rep.3:481. 10.1038/bonekey.2013.215

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 331

  SinghA.RajasekaranN.HartensteinB.SzabowskiS.GajdaM.AngelP.et al (2013). Collagenase-3 (MMP-13) deficiency protects C57BL/6 mice from antibody-induced arthritis.Arthritis Res. Ther.15:R222. 10.1186/ar4423

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 332

  SirisE. S. (1998). Paget’s disease of bone.J. Bone Miner. Res.131061–1065.

  • Google Scholar

• 333

  SobueT.HakedaY.KobayashiY.HayakawaH.YamashitaK.AokiT.et al (2001). Tissue inhibitor of metalloproteinases 1 and 2 directly stimulate the bone-resorbing activity of isolated mature osteoclasts.J. Bone Miner. Res.162205–2214. 10.1359/jbmr.2001.16.12.2205

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 334

  SongI. W.LiW. R.ChenL. Y.ShenL. F.LiuK. M.YenJ. J.et al (2014). Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model.PLoS One9:e92194. 10.1371/journal.pone.0092194

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 335

  Sottrup-JensenL. (1989). Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation.J. Biol. Chem.26411539–11542.

  • Google Scholar

• 336

  SpringmanE. B.AngletonE. L.Birkedal-HansenH.Van WartH. E. (1990). Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a “cysteine switch” mechanism for activation.Proc. Natl. Acad. Sci. U.S.A.87364–368. 10.1073/pnas.87.1.364

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 337

  Stahle-BackdahlM.SandstedtB.BruceK.LindahlA.JimenezM. G.VegaJ. A.et al (1997). Collagenase-3 (MMP-13) is expressed during human fetal ossification and re-expressed in postnatal bone remodeling and in rheumatoid arthritis.Lab. Invest.76717–728.

  • Pubmed Abstract
  • Google Scholar

• 338

  SternlichtM. D.WerbZ. (2001). How matrix metalloproteinases regulate cell behavior.Annu. Rev. Cell. Dev. Biol.17463–516. 10.1146/annurev.cellbio.17.1.463

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 339

  StickensD.BehonickD. J.OrtegaN.HeyerB.HartensteinB.YuY.et al (2004). Altered endochondral bone development in matrix metalloproteinase 13-deficient mice.Development1315883–5895. 10.1242/dev.01461

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 340

  SugimotoK.NakamuraT.TokunagaT.UeharaY.OkadaT.TaniwakiT.et al (2018). Matrix metalloproteinase promotes elastic fiber degradation in ligamentum flavum degeneration.PLoS One13:e0200872. 10.1371/journal.pone.0200872

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 341

  SuhW. K.WangS. X.JheonA. H.MorenoL.YoshinagaS. K.GanssB.et al (2004). The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization.Proc. Natl. Acad. Sci. U.S.A.10112969–12973. 10.1073/pnas.0405259101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 342

  SulkalaM.TervahartialaT.SorsaT.LarmasM.SaloT.TjaderhaneL. (2007). Matrix metalloproteinase-8 (MMP-8) is the major collagenase in human dentin.Arch. Oral Biol.52121–127. 10.1016/j.archoralbio.2006.08.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 343

  SunB.SunJ.HanX.LiuH.LiJ.DuJ.et al (2016). Immunolocalization of MMP 2, 9 and 13 in prednisolone induced osteoporosis in mice.Histol. Histopathol.31647–656. 10.14670/HH-11-702

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 344

  SundaramK.NishimuraR.SennJ.YoussefR. F.LondonS. D.ReddyS. V. (2007). RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation.Exp. Cell Res.313168–178. 10.1016/j.yexcr.2006.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 345

  TakayanagiH.KimS.KogaT.NishinaH.IsshikiM.YoshidaH.et al (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.Dev. Cell3889–901. 10.1016/s1534-5807(02)00369-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 346

  TakemuraY.MoriyamaY.AyukawaY.KurataK.RakhmatiaY. D.KoyanoK. (2019). Mechanical loading induced osteocyte apoptosis and connexin 43 expression in three-dimensional cell culture and dental implant model.J. Biomed. Mater. Res. A107815–827. 10.1002/jbm.a.36597

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 347

  TamamuraY.OtaniT.KanataniN.KoyamaE.KitagakiJ.KomoriT.et al (2005). Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification.J. Biol. Chem.28019185–19195. 10.1074/jbc.m414275200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 348

  TanakaS.TakahashiN.UdagawaN.TamuraT.AkatsuT.StanleyE. R.et al (1993). Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors.J. Clin. Invest.91257–263. 10.1172/jci116179

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 349

  Tanaka-KamiokaK.KamiokaH.RisH.LimS. S. (1998). Osteocyte shape is dependent on actin filaments and osteocyte processes are unique actin-rich projections.J. Bone Miner. Res.131555–1568. 10.1359/jbmr.1998.13.10.1555

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 350

  TangS. Y.HerberR. P.HoS. P.AllistonT. (2012). Matrix metalloproteinase-13 is required for osteocytic perilacunar remodeling and maintains bone fracture resistance.J. Bone Miner. Res.271936–1950. 10.1002/jbmr.1646

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 351

  TangY.RoweR. G.BotvinickE. L.KurupA.PutnamA. J.SeikiM.et al (2013). MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.Dev. Cell25402–416. 10.1016/j.devcel.2013.04.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 352

  TangY.WuX.LeiW.PangL.WanC.ShiZ.et al (2009). TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation.Nat. Med.15757–765. 10.1038/nm.1979

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 353

  TauroM.LynchC. C. (2018). Cutting to the Chase: How matrix metalloproteinase- 2 activity controls breast-cancer-to-bone metastasis.Cancers10:E185. 10.3390/cancers10060185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 354

  TeitelbaumS. L. (2000). Bone resorption by osteoclasts.Science2891504–1508. 10.1126/science.289.5484.1504

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 355

  TeitelbaumS. L. (2007). Osteoclasts: what do they do and how do they do it?Am. J. Pathol.170427–435. 10.2353/ajpath.2007.060834

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 356

  TeitelbaumS. L.Abu-AmerY.RossF. P. (1995). Molecular mechanisms of bone resorption.J. Cell Biochem.591–10.

  • Pubmed Abstract
  • Google Scholar

• 357

  TeitelbaumS. L.RossF. P. (2003). Genetic regulation of osteoclast development and function.Nat. Rev. Genet.4638–649. 10.1038/nrg1122

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 358

  TesterA. M.WalthamM.OhS. J.BaeS. N.BillsM. M.WalkerE. C.et al (2004). Pro-matrix metalloproteinase-2 transfection increases orthotopic primary growth and experimental metastasis of MDA-MB-231 human breast cancer cells in nude mice.Cancer Res.64652–658. 10.1158/0008-5472.can-0384-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 359

  TetiA.BlairH. C.SchlesingerP.GranoM.Zambonin-ZalloneA.KahnA. J.et al (1989). Extracellular protons acidify osteoclasts, reduce cytosolic calcium, and promote expression of cell-matrix attachment structures.J. Clin. Invest.84773–780. 10.1172/jci114235

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 360

  ThiolloyS.HalpernJ.HoltG. E.SchwartzH. S.MundyG. R.MatrisianL. M.et al (2009). Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis.Cancer Res.696747–6755. 10.1158/0008-5472.CAN-08-3949

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 361

  ThompsonP. D.ClarksonP.KarasR. H. (2003). Statin-associated myopathy.JAMA2891681–1690.

  • Pubmed Abstract
  • Google Scholar

• 362

  TianE.ZhanF.WalkerR.RasmussenE.MaY.BarlogieB.et al (2003). The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.N. Engl. J. Med.3492483–2494. 10.1056/nejmoa030847

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 363

  TokitoA.JougasakiM. (2016). Matrix metalloproteinases in non-neoplastic disorders.Int. J. Mol. Sci.17:1178. 10.3390/ijms17071178

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 364

  TondraviM. M.McKercherS. R.AndersonK.ErdmannJ. M.QuirozM.MakiR.et al (1997). Osteopetrosis in mice lacking haematopoietic transcription factor PU.1.Nature38681–84. 10.1038/386081a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 365

  ToyosawaS.OyaK.SatoS.IshidaK. (2012). Osteocyte and DMP1.Clin. Calcium22713–720.

  • Pubmed Abstract
  • Google Scholar

• 366

  TozumT. F.OppenlanderM. E.Koh-PaigeA. J.RobinsD. M.McCauleyL. K. (2004). Effects of sex steroid receptor specificity in the regulation of skeletal metabolism.Calcif. Tissue Int.7560–70. 10.1007/s00223-004-0119-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 367

  TroebergL.NagaseH. (2012). Proteases involved in cartilage matrix degradation in osteoarthritis.Biochim. Biophys. Acta1824133–145. 10.1016/j.bbapap.2011.06.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 368

  TuysuzB.MosigR.AltunG.SancakS.GlucksmanM. J.MartignettiJ. A. (2009). A novel matrix metalloproteinase 2 (MMP2) terminal hemopexin domain mutation in a family with multicentric osteolysis with nodulosis and arthritis with cardiac defects.Eur. J. Hum. Genet.17565–572. 10.1038/ejhg.2008.204

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 369

  UdagawaN.TakahashiN.JimiE.MatsuzakiK.TsurukaiT.ItohK.et al (1999). Osteoblasts/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor/RANKL but not macrophage colony-stimulating factor: receptor activator of NF-kappa B ligand.Bone25517–523. 10.1016/s8756-3282(99)00210-0

  • CrossRef
  • Google Scholar

• 370

  VaananenH. K.HortonM. (1995). The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure.J. Cell Sci.1082729–2732.

  • Google Scholar

• 371

  Van WartH. E.Birkedal-HansenH. (1990). The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family.Proc. Natl. Acad. Sci. U.S.A.875578–5582. 10.1073/pnas.87.14.5578

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 372

  VandenbrouckeR. E.LibertC. (2014). Is there new hope for therapeutic matrix metalloproteinase inhibition?Nature Rev. Drug Discov.13904–927. 10.1038/nrd4390

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 373

  VandoorenJ.Van DammeJ.OpdenakkerG. (2014). On the structure and functions of gelatinase B/matrix metalloproteinase-9 in neuroinflammation.Prog. Brain Res.214193–206. 10.1016/B978-0-444-63486-3.00009-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 374

  VeidalS. S.LarsenD. V.ChenX.SunS.ZhengQ.Bay-JensenA. C.et al (2012). MMP mediated type V collagen degradation (C5M) is elevated in ankylosing spondylitis.Clin. Biochem.45541–546. 10.1016/j.clinbiochem.2012.02.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 375

  VelascoG.PendasA. M.FueyoA.KnäuperV.MurphyG.Lopez-OtınC. (1999). Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members.J. Biol. Chem.2744570–4576. 10.1074/jbc.274.8.4570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 376

  VisseR.NagaseH. (2003). Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry.Circ. Res.92827–839. 10.1161/01.res.0000070112.80711.3d

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 377

  Vivinus-NebotM.RousselleP.BreittmayerJ. P.CenciariniC.Berrih-AkninS.SpongS.et al (2004). Mature human thymocytes migrate on laminin-5 with activation of metalloproteinase-14 and cleavage of CD44.J. Immunol.1721397–1406. 10.4049/jimmunol.172.3.1397

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 378

  VuT. H.ShipleyJ. M.BergersG.BergerJ. E.HelmsJ. A.HanahanD.et al (1998). MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypetrophic chondrocytes.Cell93411–422. 10.1016/s0092-8674(00)81169-1

  • CrossRef
  • Google Scholar

• 379

  WadaT.NakashimaT.Oliveira-dos-SantosA. J.GasserJ.HaraH.SchettG.et al (2005). The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis.Nat Med.11394–399. 10.1038/nm1203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 380

  Wagenaar-MillerR. A.EngelholmL. H.GavardJ.YamadaS. S.GutkindJ. S.BehrendtN.et al (2007). Complementary roles of intracellular and pericellular collagen degradation pathways in vivo.Mol. Cell. Biol.276309–6322. 10.1128/mcb.00291-07

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 381

  WestbroekI.De RooijK. E.NijweideP. J. (2002). Osteocyte-specific monoclonal antibody MAb OB7.3 is directed against Phex protein.J. Bone Miner. Res.17845–853. 10.1359/jbmr.2002.17.5.845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 382

  WiebeS. H.HafeziM.SandhuH. S.SimsS. M.DixonS. J. (1996). Osteoclast activation in inflammatory periodontal diseases.Oral Dis.2167–180. 10.1111/j.1601-0825.1996.tb00218.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 383

  WuH.DuJ.ZhengQ. (2008). Expression of MMP-1 in cartilage and synovium of experimentally induced rabbit ACLT traumatic osteoarthritis: immunohistochemical study.Rheumatol. Int.2931–36. 10.1007/s00296-008-0636-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 384

  WutzlA.RaunerM.SeemannR.MillesiW.KreplerP.PietschmannP.et al (2010). Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro.J. Orthop. Res.281431–1439. 10.1002/jor.21144

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 385

  XianL.WuX.PangL.LouM.RosenC. J.QiuT.et al (2012). Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells.Nat. Med.181095–1101. 10.1038/nm.2793

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 386

  XueM.MarchL.SambrookP. N.JacksonC. J. (2007). Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis.Arthritis Rheum.562864–2874. 10.1002/art.22844

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 387

  XueM.McKelveyK.ShenK.MinhasN.MarchL.ParkS. Y.et al (2014). Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation.Rheumatology532270–2279. 10.1093/rheumatology/keu254

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 388

  YamadaY.AndoF.NiinoN.ShimokataH. (2004). Association of a polymorphism of the matrix metalloproteinase-9 gene with bone mineral density in japanese men.Metabolism53135–137. 10.1016/j.metabol.2003.09.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 389

  YamagiwaH.TokunagaK.HayamiT.HatanoH.UchidaM.EndoN.et al (1999). Expression of metalloproteinase-13 (collagenase-3) is induced during fracture healing in mice.Bone25197–203. 10.1016/s8756-3282(99)00157-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 390

  YamaguchiA.KomoriT.SudaT. (2000). Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1.Endocr. Rev.21393–411. 10.1210/edrv.21.4.0403

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 391

  YeeC. S.SchurmanC. A.WhiteC. R.AllistonT. (2019). Investigating osteocytic perilacunar/canalicular remodeling.Curr. Osteoporos Rep.17157–168. 10.1007/s11914-019-00514-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 392

  ZanklA.BonafeL.CalcaterraV.Di RoccoM.Superti-FurgaA. (2005). Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.Clin. Genet.67261–266. 10.1111/j.1399-0004.2004.00402.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 393

  ZengY.RosboroughR. C.LiY.GuptaA. R.BennettJ. (1998). Temporal and spatial regulation of gene expression mediated by the promoter for the human tissue inhibitor of metalloproteinases-3 (TIMP-3)-encoding gene.Dev. Dyn.211228–237. 10.1002/(sici)1097-0177(199803)211:3<228::aid-aja4>3.0.co;2-j

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 394

  ZhangB.HenneyA.ErikssonP.HamstenA.WatkinsH.YeS. (1999). Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1.Hum. Genet.105418–423. 10.1007/s004399900167

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 395

  ZhangJ. F.WangG. L.ZhouZ. J.FangX. Q.ChenS.FanS. W. (2018). Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and interleukins in vertebral cartilage endplate.Orthop. Surg.10306–311. 10.1111/os.12409

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 396

  ZhangK.Barragan-AdjemianC.YeL.KothaS.DallasM.LuY.et al (2006). E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation.Mol. Cell Biol.264539–4552. 10.1128/mcb.02120-05

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 397

  ZhangW.YangN.ShiX. M. (2008). Regulation of mesenchymal stem cell osteogenic differentiation by glucocorticoid-induced leucine zipper (GILZ).J. Biol. Chem.2834723–4729. 10.1074/jbc.m704147200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 398

  ZhaoH.CaiG.DuJ.XiaZ.WangL.ZhuT. (1997). Expression of matrix metalloproteinase-9 mRNA in osteoporotic bone tissues.J. Tongji. Med. Univ.1728–31. 10.1007/bf02887998

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 399

  ZhaoS.ZhangY. K.HarrisS.AhujaS. S.BonewaldL. F. (2002). MLO-Y4 osteocyte-like cells support osteoclast formation and activation.J. Bone Miner. Res.172068–2079. 10.1359/jbmr.2002.17.11.2068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 400

  ZhengH.LiuJ.TycksenE.NunleyR.McAlindenA. (2019). MicroRNA-181a/b-1 over-expression enhances osteogenesis by modulating PTEN/PI3K/AKT signaling and mitochondrial metabolism.Bone12392–102. 10.1016/j.bone.2019.03.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 401

  ZhouZ.ApteS. S.SoininenR.CaoR.BaakliniG. Y.RauserR. W.et al (2000). Impaired endochondral ossification and angiogenesis in mice deficient in membrane type matrix metalloproteinase I.Proc. Natl. Acad. Sci. U.S.A.974052–4057. 10.1073/pnas.060037197

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 402

  ZuckerS.CaoJ.ChenW. T. (2000). Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment.Oncogene196642–6650. 10.1038/sj.onc.1204097

  • Pubmed Abstract
  • CrossRef
  • Google Scholar