Mini Review ARTICLE
Multiple Roles of Angiopoietin-Like 4 in Osteolytic Disease
- Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
Hypoxia and the hypoxia-inducible factor (HIF) transcription factor drive pathological bone loss in conditions including rheumatoid arthritis (RA), osteoarthritis, osteoporosis, primary bone tumours, and bone metastatic cancer. There is therefore considerable interest in determining the function(s) of HIF-induced genes in these pathologies. Angiopoietin-like 4 (ANGPTL4) is an adipose-derived, HIF-1α- and PPARγ-induced gene that was originally discovered as an endocrine and autocrine/paracrine regulator of lipid metabolism. Given the inverse relationship between bone adiposity and fracture risk, ANGPTL4 might be considered a good candidate for mediating the downstream effects of HIF-1α relevant to osteolytic disease. This review will consider the possible roles of ANGPTL4 in regulation of osteoclast-mediated bone resorption, cartilage degradation, angiogenesis, and inflammation, focusing on results obtained in the study of RA. Possible roles in other musculoskeletal pathologies will also be discussed. This will highlight ANGPTL4 as a regulator of multiple disease processes, which could represent a novel therapeutic target in osteolytic musculoskeletal disease.
Bone remodelling is a carefully regulated process that requires the coordinated actions of osteoclasts, which resorb bone, and osteoblasts, which form new mineralised bone. The remodelling process is essential for formation, development, and maintenance of the skeleton. Disruption of the balance between bone formation and bone resorption in favour of osteoclast overactivation results in pathological bone loss, as evident in osteolytic conditions including rheumatoid arthritis (RA) (1, 2), osteoporosis (3), primary bone tumours (4–6), and bone metastatic cancer (7). The same conditions are associated with microenvironmental hypoxia, which correlates with disease progression and reduced chance of survival (8–11).
Hypoxia-inducible factor (HIF) is a critical mediator of cellular responses to hypoxia. HIF is a heterodimeric transcription factor that is regulated at the level of the stability and transcriptional activity of the alpha subunits (HIF-1α, HIF-2α). In normoxic conditions, HIF-α is posttranslationally hydroxylated by the prolyl hydroxylase domain enzymes (PHD1–3), which target it for proteasomal degradation, and asparagine hydroxylase factor-inhibiting HIF (FIH), which inhibits any remaining transcriptional activity. However these enzymes are oxygen dependent, allowing HIF-α to stabilise under hypoxia and bind to the hypoxia-response element of HIF target genes to initiate hypoxia-induced transcription (12).
As hypoxia and HIF drive disease progression in various musculoskeletal conditions, there is considerable interest in the pathological function(s) of HIF-induced genes. Angiopoietin-like 4 (ANGPTL4) is a secreted adipokine and a member of a family of eight angiopoietin-like (ANGPTL1–8) proteins. Hypoxic induction of ANGPTL4 by the HIF-1α isoform of HIF was initially described in cardiomyocytes (13) but also occurs in other musculoskeletal cells including adipocytes (14), endothelial cells (15), chondrocytes (16), monocytes, osteoclasts, and osteoblasts (17).
Despite being structurally similar to the angiopoietins, ANGPTLs do not bind either the Tie1 or Tie2 receptor and have no identified cognate receptors, rendering them orphan ligands. Full-length ANGPTL4 (flANGPTL4) contains a signal peptide mediating its secretion, an N-terminal coiled-coil domain, a linker, and a C-terminal fibrinogen-like domain (18). This 406 amino acid glycosylated protein, with a molecular mass of approximately 65 kDa, can be proteolytically cleaved at the linker region by proprotein convertases to generate N-terminal (nANGPTL4) and C-terminal (cANGPTL4) fragments (19). Both flANGPTL4 and nANGPTL4 oligomerise in vivo, whereas cANGPTL4 dissociates into monomers (20, 21). Cleavage of ANGPTL4 appears to be tissue dependent; the human liver secretes cleaved ANGPTL4, whereas adipocytes secrete the full-length form (22, 23). The three forms of ANGPTL4 exert distinct physiological functions; regulation of lipid metabolism is the primary function of N-terminal ANGPTL4 (20, 22).
Angiopoietin-like 4 was initially discovered as a central regulator of lipid metabolism that was induced by PPARγ under fasting conditions, accounting for its initial nomenclature of fasting-induced adipose factor (FIAF) (24). It is also transcriptionally regulated by PPARα and β/δ (22, 25). ANGPTL4 is the primary physiological regulator of lipoprotein lipase (LPL) activity, stimulating conversion of catalytically active LPL dimers into inactive monomers. This causes increased levels of plasma triacylglycerol, specifically VLDL, and non-esterified fatty acids, with subsequent depletion of adipose tissue stores (26, 27).
The relationship between fat and bone is complex. Body weight positively associates with bone mineral density, but bone marrow adiposity and bone mass exhibit an inverse relationship, and many conditions associated with increased fracture risk display increased marrow adiposity (28, 29). As an adipose-derived factor, it seems likely that ANGPTL4 might also play physiological and pathological roles within the skeleton. This review will consider possible roles for ANGPTL4 in osteolytic disease, particularly focussing on the pathogenesis of RA.
Pathological Functions of ANGPTL4 in RA
Rheumatoid arthritis is a chronic inflammatory disease characterised by the formation of a hyperplastic synovium containing synovial fibroblasts, macrophages, CD4+ T cells, B cells, and plasma cells. The synovium is locally invasive and, alongside activated osteoclasts, erodes articular cartilage and subchondral bone causing progressive destruction of the affected joints, associated with joint pain and compromised function. Synovial hyperplasia increases the distance between synovial lining cells and the nearest blood vessel. This ultimately exceeds the diffusion limit for oxygen, resulting in the development of a hypoxic microenvironment within the RA synovium that correlates with the intensity of inflammation and is a poor prognostic indicator (11). Both HIF-1α and HIF-2α are overexpressed in RA, and the HIF pathway is considered a target for therapy (30).
Angiopoietin-like 4 overexpression was first described in stromal fibroblasts within the joints of mice with collagen-induced arthritis (31). It has since been reported in RA articular chondrocytes (16) and in stromal fibroblasts, macrophages, plasma cells, endothelial cells, and osteoclasts within the hyperplastic synovium (32). Such widespread induction could rapidly provide a large local pool of ANGPTL4 to regulate a variety of disease processes. ANGPTL4 was also elevated in the serum and synovial fluid of RA patients in comparison with non-inflammatory osteoarthritis (OA) or normal controls (32).
Osteoclast-Mediated Bone Resorption
Osteoclasts are large multi-nucleated cells that form by fusion of CD14+ monocytic precursors in the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL). Osteoclast differentiation is stimulated by hypoxia–reoxygenation, rather than hypoxia per se, and is not apparently dependent on HIF (33). However, bone resorption by mature osteoclasts is induced by hypoxia in a HIF-1α-dependent manner in vitro (17, 34–36) and in vivo (10). Similarly, PPARγ promotes osteoclast differentiation and bone resorption (37).
We reported hypoxia-inducible, HIF-1α-dependent induction of ANGPTL4 by human osteoclasts, as well as monocytes and osteoblasts (17). Exposure of mature human osteoclasts to flANGPTL4 stimulated a twofold to threefold increase in lacunar bone resorption that was independent of RANKL, while not affecting osteoclast differentiation (17). In contrast, Lin et al. reported neither flANGPTL4 nor cANGPTL4 to affect either murine osteoclast formation or bone resorption, whereas nANGPTL4 inhibited both activities (38). Effects of nANGPTL4 were apparently mediated by reduced expression of RANKL, M-CSF, and connective tissue growth factor (CTGF) by stromal cells within the marrow culture, resulting in reduced expression of osteoclastogenic NFATc1 and DC-STAMP (38). The differences between the two studies may be due to interspecies effects or to the different osteoclast culture methods used.
It is currently unknown whether ANGPTL4 cleavage occurs in skeletal tissue, although adipocytes, which are numerous in the bone marrow, secrete the full-length protein (22, 23). We could detect only flANGPTL4 in human osteoclasts, but primary human osteoblasts produced both flANGPTL4 and cANGPTL4 in vitro (17). In support of a role for ANGPTL4 in osteoclast-mediated bone resorption, we correlated high serum concentrations of ANGPTL4 in RA with elevated levels of circulating RANKL, a serum marker of bone resorption (32).
Articular cartilage is composed predominantly of chondrocytes and is avascular, meaning that the chondrocytes normally reside in a hypoxic environment. Destruction of articular cartilage in RA is associated with increased expression and activity of matrix metalloproteinases (MMPs). In vitro work on RA synovial fibroblasts describes hypoxia- and HIF-1α-driven induction of MMP expression by these cells (30), which could drive hypoxic enhancement of cartilage destruction.
Angiopoietin-like 4 might mediate a component of the hypoxic induction of MMPs. RA articular chondrocytes cultured in vitro exhibited hypoxia-inducible ANGPTL4 secretion. Similarly, normal human cartilage expressed little ANGPTL4 whereas strong cytoplasmic staining of articular chondrocytes occurred in more severely hypoxic rheumatoid cartilage (16). Exposure of articular chondrocytes to flANGPTL4 increased expression of MMP-1 and MMP-3 (16). cANGPTL4 also promoted cartilage matrix remodelling during chondrogenic differentiation, inhibiting aggrecan and type II collagen expression and inducing expression of MMP-1, MMP-3, and MMP-13 (39). ANGPTL4 might therefore contribute to cartilage matrix destruction in RA via induction of MMPs.
Angiopoietin-like 4 could also exacerbate cartilage destruction via promotion of osteoclast-mediated resorption pathways. Multi-nucleated cells resorbing cartilage in RA have an osteoclast-like phenotype, and human monocyte-derived osteoclasts can digest cartilage matrix in vitro (40, 41). As the erosive effect of osteoclasts on cartilage appear to be MMP-mediated (41), ANGPTL4 might induce cartilage erosion in RA, via effects on MMP production and osteoclast activation, to increase joint destruction.
Synovial angiogenesis in RA probably occurs as a consequence of synovial hypoxia. Hypoxia-induced HIF induces expression of pro-angiogenic mediators including vascular endothelial growth factor (VEGF), interleukin 8 (IL-8), macrophage inflammatory protein 3α (MIP-3a), and stromal-derived factor 1 (SDF-1). The increased blood supply transports nutrients and immune cells to the inflammatory synovium but cannot provide sufficient oxygen to negate the hypoxic stimulus (30, 42). Increased ANGPTL4 expression during early stages of murine collagen-induced arthritis occurred specifically in stromal fibroblasts adjacent to blood vessels, suggestive of a role in angiogenesis (31).
Besides lipid regulation, the other main function of ANGPTL4 is vascular, with roles in angiogenesis and vessel permeability mediated by flANGPTL4 and cANGPTL4. ANGPTL4 is reported to inhibit endothelial apoptosis and stimulate endothelial cell migration and tube formation, so inducing angiogenesis in vivo (15, 18, 25, 31, 43–47). However, anti-angiogenic effects are also reported (48–52). The complexity of the response is highlighted by reports from the same group describing pro- and anti-angiogenic effects of ANGPTL4 (15, 49, 53) and by reports of opposing effects for both flANGPTL4 and cANGPTL4. There is similar controversy regarding whether ANGPTL4 promotes or inhibits vascular permeability (54, 55).
Synovitis is a major characteristic of RA and HIF acts as a key regulator of the associated inflammation, being highly expressed in immune cells, especially macrophages, in the RA synovium (42, 56). Conditional knockout of HIF-1α in myeloid cells in a murine model of RA significantly reduced synovial inflammation and disease progression (57). Similarly, HIF-1α played a critical role in hypoxia-induced synovial hyperplasia and inflammatory cell infiltration in murine collagen-induced arthritis (58). HIF also induces expression of inflammatory cytokines including IL-6, IL-8, TNF-α, and IL-1β in rheumatoid synovial fibroblasts (59).
Angiopoietin-like 4 is also overexpressed in inflammation. ANGPTL4 was induced by IL-1β in osteoblasts (60) and by IL-1β, TNF-α, IFNγ, or LPS in adipocytes (61). LPS activates toll-like receptor 4 (TLR4), one of the TLR family of pattern recognition receptors that regulate inflammatory responses in RA. Treatment of mice with LPS induced ANGPTL4 expression in adipose tissue and muscle that was dependent on TLR4 signalling (61, 62). Additionally, circulating levels of ANGPTL4 positively correlate with the inflammatory marker C reactive protein in patients with inflammatory conditions such as metabolic syndrome, type 2 diabetes, and chronic obstructive pulmonary disease (63–65) as well as within the general population (66). These extra-articular conditions often accompany RA and also relate to insulin resistance, leading to suggestions that ANGPTL4 might represent a molecular link between insulin resistance and RA (67).
However, few direct effects of ANGPTL4 on inflammation are yet described. ANGPTL4 protected against the lethal inflammation induced by dietary saturated fat in mice, by reducing inflammatory gene expression and macrophage foam cell formation (68). However, it was shown to expand the proliferation and formation of myeloid progenitors (69). Further studies are required to determine whether ANGPTL4 mediates pro- or anti-inflammatory effects in RA.
ANGPTL4 in Other Musculoskeletal Conditions
Cancer in Bone
Angiopoietin-like 4 is overexpressed in the hypoxic peri-necrotic regions of solid tumours and has central roles in cancer growth, anoikis resistance, angiogenesis, and metastasis (54, 55). These pro-tumourigenic mechanisms are covered in other reviews, although pro-metastatic effects generally relate to promotion of angiogenesis and vascular permeability.
There are, however, few descriptions of ANGPTL4 in primary bone tumours or cancer metastasis to bone. Breast cancer, prostate cancer, and lung cancer most commonly metastasise to bone. ANGPTL4 has only been described in relation to breast cancer metastasis, but its pro-metastatic role was largely related to distant lung or brain metastases with little mention of bone metastatic disease.
Angiopoietin-like 4 is part of gene signatures associated with distant metastasis (70) and tumour aggressiveness (71) in breast cancer and is overexpressed in high-grade breast carcinoma (72). However, bone metastatic disease was not apparently included in these analyses. Padua et al. showed ANGPTL4 knock-down to reduce breast cancer lung metastasis, but with no effect on either local lymph node metastasis or bone metastasis (73). Similarly, ANGPTL4 overexpression increased breast cancer lung metastasis by MDA-MB-231 cells (74).
Osteosarcoma, Ewing’s sarcoma, and chondrosarcoma are the most common primary bone tumours, and HIF promotes disease progression in each (75–78), as well as in giant cell tumour of bone (GCTB) (79) and multiple myeloma (80). We detected ANGPTL4 expression in osteoclasts and mononuclear cells present in GCTB (17). Contact of multiple myeloma cells with mesenchymal stem cells or pre-osteoblasts increased expression of ANGPTL4 in the non-malignant population and enhanced myeloma cell adhesion (81). Considering the pro-tumourigenic effects of HIF in these cancers, ANGPTL4 might be expected to also exert tumour-promoting effects, but this has not been investigated.
Bone Fracture and Osteoporosis
Hopwood et al. compared gene expression in trabecular bone from the proximal femur of osteoporotic (OP) individuals who had suffered a fragility fracture of the femur with bone from age-matched controls (82). Three groups of genes overexpressed in OP were involved in osteoclast differentiation and function, inhibition of osteoblast differentiation and mineralisation, or were genes involved in adipogenesis, lipid metabolism, glucose metabolism, and insulin resistance. ANGPTL4 was one of these genes (82) and, with roles in all three disease processes, could be considered a critical mediator of OP pathology.
Angiopoietin-like 4 overexpression occurred in newly mineralising osteoblasts in a murine model of stabilised femoral fracture (83), and ANGPTL4 mRNA expression was elevated during osteogenic differentiation of MC3T3-E1 and periodontal ligament cells (83, 84). Exogenous ANGPTL4 enhanced osteoblastogenic gene expression in MC3T3-E1 cells but did not affect mineralisation (83). In osteoblastic Saos2 cells, high ANGPTL4 concentrations promoted proliferation but inhibited osteoblastogenesis, whereas lower concentrations promoted osteoblast differentiation (17). Further definition of the effects of ANGPTL4 on osteoblast formation and function is still required.
Overexpression of ANGPTL4 also occurs in OA. Microarray studies described ANGPTL4 overexpression in cartilage from non-traumatic osteonecrosis of the femoral head, OA (85), and porcine osteochondrosis (86) versus control cartilage, as well as in damaged versus undamaged cartilage from individuals with anteromedial knee OA (87). We observed immunohistochemical overexpression of ANGPTL4 within the OA synovium, although to a lesser extent than in RA. However, secretion of ANGPTL4 was not elevated in non-inflammatory OA serum (32). Coupled with ANGPTL4-mediated induction of MMP expression and cartilage matrix remodelling in chondrocytes (16, 39), this suggests ANGPTL4 as a potential mediator of pathogenic cartilage destruction in OA.
Multiple physiological and pathological roles associated with osteolytic disease are ascribed to ANGPTL4 including promotion of osteoclast-mediated bone resorption, cartilage degradation, angiogenesis and vascular permeability, as well as tumour cell growth and metastasis. However research into the musculoskeletal functions of ANGPTL4 is in its infancy, resulting in some controversy or lack of comprehensive research regarding the precise role(s) of ANGPTL4 in different disease processes. This is further complicated by the assignation of alternative cellular functions to the three cleavage products of ANGPTL4. Direct investigation of effects of ANGPTL4 in the varied and different pathologies is yet to be performed and will need to consider the different cleavage products as well as combined effects of modifying multiple disease processes on overall disease activity.
Despite this, ANGPTL4 must be considered an attractive potential therapeutic target, blockade of which might dramatically affect disease progression via inhibition of multiple disease processes. HIF-1α itself is considered a good target for treatment of RA. However, advancement of this hypothesis is limited by the lack of drugs that specifically block the HIF pathway, precluding detailed analysis of specific effects of HIF inhibition on RA progression. Neutralising anti-ANGPTL4 antibodies have been developed for use in murine models of disease (88, 89) and, as interest grows in targeting ANGPTL4 therapeutically, humanised neutralising anti-ANGPTL4 antibodies will likely also be developed. With the ability to specifically inhibit ANGPTL4-mediated disease processes, the path is open for new research into emerging effects of this adipokine in osteolytic disease.
HK conceived the review, acquired, and critically analysed the literature, and wrote and critically revised the manuscript.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author thanks Prof. Nick Athanasou for critical reading of the manuscript.
This work was supported by grants from Arthritis Research UK (MP/19200) and the Bone Cancer Research Trust (4716).
2. Gough A, Sambrook P, Devlin J, Huissoon A, Njeh C, Robbins S, et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol (1998) 25(7):1282–9.
4. Endo-Munoz L, Evdokiou A, Saunders NA. The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim Biophys Acta (2012) 1826(2):434–42. doi:10.1016/j.bbcan.2012.07.003
10. Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, et al. HIF1alpha is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. Proc Natl Acad Sci U S A (2013) 110(41):16568–73. doi:10.1073/pnas.1308755110
13. Belanger AJ, Lu HW, Date L, Liu LX, Vincent KA, Akita GY, et al. Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1 alpha. J Mol Cell Cardiol (2002) 34(7):765–74. doi:10.1006/jmcc.2002.2021
14. Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflugers Arch (2007) 455(3):479–92. doi:10.1007/s00424-007-0301-8
15. Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, et al. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol (2003) 162(5):1521–8. doi:10.1016/S0002-9440(10)64285-X
16. Murata M, Yudo K, Nakamura H, Chiba J, Okamoto K, Suematsu N, et al. Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: role of angiopoietin-like-4 in the expression of matrix metalloproteinases and cartilage degradation. J Orthop Res (2009) 27(1):50–7. doi:10.1002/jor.20703
17. Knowles HJ, Cleton-Jansen AM, Korsching E, Athanasou NA. Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4. FASEB J (2010) 24(12):4648–59. doi:10.1096/fj.10-162230
18. Kim I, Kim HG, Kim H, Kim HH, Park SK, Uhm CS, et al. Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis. Biochem J (2000) 346:603–10. doi:10.1042/bj3460603
19. Lei X, Shi F, Basu D, Huq A, Routhier S, Day R, et al. Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity. J Biol Chem (2011) 286(18):15747–56. doi:10.1074/jbc.M110.217638
20. Ge HF, Yang GQ, Huang L, Motola DL, Pourbahrami T, Li C. Oligomerization and regulated proteolytic processing of angiopoietin-like protein 4. J Biol Chem (2004) 279(3):2038–45. doi:10.1074/jbc.M307583200
21. Yin W, Romeo S, Chang S, Grishin NV, Hobbs HH, Cohen JC. Genetic variation in ANGPTL4 provides insights into protein processing and function. J Biol Chem (2009) 284(19):13213–22. doi:10.1074/jbc.M900553200
22. Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, et al. The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment. J Biol Chem (2004) 279(33):34411–20. doi:10.1074/jbc.M403058200
23. Koliwad SK, Kuo T, Shipp LE, Gray NE, Backhed F, So AY, et al. Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism. J Biol Chem (2009) 284(38):25593–601. doi:10.1074/jbc.M109.025452
24. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, et al. Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem (2000) 275(37):28488–93. doi:10.1074/jbc.M004029200
25. Yoon JC, Chickering TW, Rosen ED, Dussault B, Qin YB, Soukas A, et al. Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation. Mol Cell Biol (2000) 20(14):5343–9. doi:10.1128/MCB.20.14.5343-5349.2000
31. Hermann LM, Pinkerton M, Jennings K, Yang L, Grom A, Sowders D, et al. Angiopoietin-like-4 is a potential angiogenic mediator in arthritis. Clin Immunol (2005) 115(1):93–101. doi:10.1016/j.clim.2004.12.002
32. Swales C, Athanasou NA, Knowles HJ. Angiopoietin-like 4 is over-expressed in rheumatoid arthritis patients: association with pathological bone resorption. PLoS One (2014) 9(10):e109524. doi:10.1371/journal.pone.0109524
36. Morten KJ, Badder L, Knowles HJ. Differential regulation of HIF-mediated pathways increases mitochondrial metabolism and ATP production in hypoxic osteoclasts. J Pathol (2013) 229(5):755–64. doi:10.1002/path.4159
39. Mathieu M, Iampietro M, Chuchana P, Guerit D, Djouad F, Noel D, et al. Involvement of angiopoietin-like 4 in matrix remodeling during chondrogenic differentiation of mesenchymal stem cells. J Biol Chem (2014) 289(12):8402–12. doi:10.1074/jbc.M113.539825
40. Knowles HJ, Moskovsky L, Thompson MS, Grunhen J, Cheng X, Kashima TG, et al. Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption. Virchows Arch (2012) 461(2):205–10. doi:10.1007/s00428-012-1274-3
41. Lindstrom E, Grabowska U, Athanasou N, Fuller K, Chambers TJ. Inhibition of CTX-II release by cathepsin K inhibition in vivo but not in vitro suggests that anti-resorptive therapy protects cartilage. Bone Research Society Annual Meeting 2016; Liverpool. Frontiers in Endocrinology: Bone Research. (2016).
43. Tian LF, Zhou J, Casimiro MC, Liang B, Ojeifo JO, Wang M, et al. Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesis. Cancer Res (2009) 69(24):9236–44. doi:10.1158/0008-5472.can-09-2067
44. Ma T, Jham BC, Hu J, Friedman ER, Basile JR, Molinolo A, et al. Viral G protein-coupled receptor up-regulates angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi’s sarcoma. Proc Natl Acad Sci U S A (2010) 107(32):14363–8. doi:10.1073/pnas.1001065107
45. Huang RL, Teo Z, Chong HC, Zhu P, Tan MJ, Tan CK, et al. ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters. Blood (2011) 118(14):3990–4002. doi:10.1182/blood-2011-01-328716
46. Perdiguero EG, Galaup A, Durand M, Teillon J, Philippe J, Valenzuela DM, et al. Alteration of developmental and pathological retinal angiogenesis in angptl4-deficient mice. J Biol Chem (2011) 286(42):36841–51. doi:10.1074/jbc.M111.220061
47. Chong HC, Chan JS, Goh CQ, Gounko NV, Luo B, Wang X, et al. Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice. Mol Ther (2014) 22(9):1593–604. doi:10.1038/mt.2014.102
49. Cazes A, Galaup A, Chomel C, Bignon M, Brechot N, Le Jan S, et al. Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration, and sprouting and alters actin cytoskeleton. Circ Res (2006) 99(11):1207–15. doi:10.1161/01.res.0000250758.63358.91
50. Yang YH, Wang Y, Lam KS, Yau MH, Cheng KK, Zhang J, et al. Suppression of the Raf/MEK/ERK signaling cascade and inhibition of angiogenesis by the carboxyl terminus of angiopoietin-like protein 4. Arterioscler Thromb Vasc Biol (2008) 28(5):835–40. doi:10.1161/ATVBAHA.107.157776
51. Chomel C, Cazes A, Faye C, Bignon M, Gomez E, Ardidie-Robouant C, et al. Interaction of the coiled-coil domain with glycosaminoglycans protects angiopoietin-like 4 from proteolysis and regulates its antiangiogenic activity. FASEB J (2009) 23(3):940–9. doi:10.1096/fj.08-115170
53. Galaup A, Cazes A, Le Jan S, Philippe J, Connault E, Le Coz E, et al. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci U S A (2006) 103(49):18721–6. doi:10.1073/pnas.0609025103
56. Hollander AP, Corke KP, Freemont AJ, Lewis CE. Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum (2001) 44(7):1540–4. doi:10.1002/1529-0131(200107)44:7<1540::AID-ART277>3.0.CO;2-7
57. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell (2003) 112(5):645–57. doi:10.1016/S0092-8674(03)00154-5
58. Li GQ, Zhang Y, Liu D, Qian YY, Zhang H, Guo SY, et al. PI3 kinase/Akt/HIF-1alpha pathway is associated with hypoxia-induced epithelial-mesenchymal transition in fibroblast-like synoviocytes of rheumatoid arthritis. Mol Cell Biochem (2013) 372(1–2):221–31. doi:10.1007/s11010-012-1463-z
59. Hu F, Liu H, Xu L, Li Y, Liu X, Shi L, et al. Hypoxia-inducible factor-1alpha perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis. Eur J Immunol (2016) 46(3):742–51. doi:10.1002/eji.201545784
60. Noh JM, Shen C, Kim SJ, Kim MR, Kim SH, Kim JH, et al. Interleukin-1beta increases Angptl4 (FIAF) expression via the JNK signaling pathway in osteoblastic MC3T3-E1 cells. Exp Clin Endocrinol Diabetes (2015) 123(8):445–60. doi:10.1055/s-0035-1554624
61. Lu B, Moser A, Shigenaga JK, Grunfeld C, Feingold KR. The acute phase response stimulates the expression of angiopoietin like protein 4. Biochem Biophys Res Commun (2010) 391(4):1737–41. doi:10.1016/j.bbrc.2009.12.145
62. Brown R, Imran SA, Wilkinson M. Lipopolysaccharide (LPS) stimulates adipokine and socs3 gene expression in mouse brain and pituitary gland in vivo, and in N-1 hypothalamic neurons in vitro. J Neuroimmunol (2009) 209(1–2):96–103. doi:10.1016/j.jneuroim.2009.02.001
63. Muendlein A, Saely CH, Leiherer A, Fraunberger P, Kinz E, Rein P, et al. Angiopoietin-like protein 4 significantly predicts future cardiovascular events in coronary patients. Atherosclerosis (2014) 237(2):632–8. doi:10.1016/j.atherosclerosis.2014.10.028
64. Tjeerdema N, Georgiadi A, Jonker JT, van Glabbeek M, Alizadeh Dehnavi R, Tamsma JT, et al. Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes. BMJ Open Diabetes Res Care (2014) 2(1):e000034. doi:10.1136/bmjdrc-2014-000034
65. Wu YQ, Shen YC, Wang H, Zhang JL, Li DD, Zhang X, et al. Serum angiopoietin-like 4 is over-expressed in COPD patients: association with pulmonary function and inflammation. Eur Rev Med Pharmacol Sci (2016) 20(1):44–53.
66. Robciuc MR, Tahvanainen E, Jauhiainen M, Ehnholm C. Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample. J Lipid Res (2009) 51(4):824–31. doi:10.1194/jlr.M002618
68. Lichtenstein L, Mattijssen F, de Wit NJ, Georgiadi A, Hooiveld GJ, van der Meer R, et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab (2010) 12(6):580–92. doi:10.1016/j.cmet.2010.11.002
69. Schumacher A, Denecke B, Braunschweig T, Stahlschmidt J, Ziegler S, Brandenburg LO, et al. Angptl4 is upregulated under inflammatory conditions in the bone marrow of mice, expands myeloid progenitors, and accelerates reconstitution of platelets after myelosuppressive therapy. J Hematol Oncol (2015) 8:64. doi:10.1186/s13045-015-0152-2
71. Kanwar N, Hu P, Bedard P, Clemons M, McCready D, Done SJ. Identification of genomic signatures in circulating tumor cells from breast cancer. Int J Cancer (2015) 137(2):332–44. doi:10.1002/ijc.29399
72. Shafik NM, Mohamed DA, Bedder AE, El-Gendy AM. Significance of tissue expression and serum levels of angiopoietin-like protein 4 in breast cancer progression: link to NF-kappaB/P65 activity and pro-inflammatory cytokines. Asian Pac J Cancer Prev (2015) 16(18):8579–87. doi:10.7314/APJCP.2015.16.18.8579
73. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell (2008) 133(1):66–77. doi:10.1016/j.cell.2008.01.046
74. Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, et al. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene (2012) 31(14):1757–70. doi:10.1038/onc.2011.365
75. Chen C, Zhou H, Wei F, Jiang L, Liu X, Liu Z, et al. Increased levels of hypoxia-inducible factor-1alpha are associated with Bcl-xL expression, tumor apoptosis, and clinical outcome in chondrosarcoma. J Orthop Res (2011) 29(1):143–51. doi:10.1002/jor.21193
76. Hameiri-Grossman M, Porat-Klein A, Yaniv I, Ash S, Cohen IJ, Kodman Y, et al. The association between let-7, RAS and HIF-1alpha in Ewing sarcoma tumor growth. Oncotarget (2015) 6(32):33834–48. doi:10.18632/oncotarget.5616
77. Li Y, Zhang W, Li S, Tu C. Prognosis value of hypoxia-inducible factor-1alpha expression in patients with bone and soft tissue sarcoma: a meta-analysis. Springerplus (2016) 5(1):1370. doi:10.1186/s40064-016-3064-x
78. Ouyang Y, Li H, Bu J, Li X, Chen Z, Xiao T. Hypoxia-inducible factor-1 expression predicts osteosarcoma patients’ survival: a meta-analysis. Int J Biol Markers (2016) 31(3):e229–34. doi:10.5301/jbm.5000216
79. Knowles HJ, Athanasou NA. Hypoxia-inducible factor is expressed in giant cell tumour of bone and mediates paracrine effects of hypoxia on monocyte-osteoclast differentiation via induction of VEGF. J Pathol (2008) 215(1):56–66. doi:10.1002/path.2319
81. Dotterweich J, Schlegelmilch K, Keller A, Geyer B, Schneider D, Zeck S, et al. Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells – implications for myeloma bone disease. Bone (2016) 93:155–66. doi:10.1016/j.bone.2016.08.006
83. Wilson SS, Wong A, Toupadakis CA, Yellowley CE. Expression of angiopoietin-like protein 4 at the fracture site: regulation by hypoxia and osteoblastic differentiation. J Orthop Res (2015) 33(9):1364–73. doi:10.1002/jor.22898
84. Choi HD, Noh WC, Park JW, Lee JM, Suh JY. Analysis of gene expression during mineralization of cultured human periodontal ligament cells. J Periodontal Implant Sci (2011) 41(1):30–43. doi:10.5051/jpis.2011.41.1.30
85. Wang W, Liu Y, Hao J, Zheng S, Wen Y, Xiao X, et al. Comparative analysis of gene expression profiles of hip articular cartilage between non-traumatic necrosis and osteoarthritis. Gene (2016) 591(1):43–7. doi:10.1016/j.gene.2016.06.058
86. Rangkasenee N, Murani E, Schellander K, Cinar MU, Ponsuksili S, Wimmers K. Gene expression profiling of articular cartilage reveals functional pathways and networks of candidate genes for osteochondrosis in pigs. Physiol Genomics (2013) 45(18):856–65. doi:10.1152/physiolgenomics.00055.2013
87. Snelling S, Rout R, Davidson R, Clark I, Carr A, Hulley PA, et al. A gene expression study of normal and damaged cartilage in anteromedial gonarthrosis, a phenotype of osteoarthritis. Osteoarthritis Cartilage (2014) 22(2):334–43. doi:10.1016/j.joca.2013.12.009
88. Drager LF, Yao Q, Hernandez KL, Shin MK, Bevans-Fonti S, Gay J, et al. Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4. Am J Respir Crit Care Med (2013) 188(2):240–8. doi:10.1164/rccm.201209-1688OC
Keywords: angiopoietin-like 4, bone resorption, cartilage degradation, angiogenesis, inflammation, rheumatoid arthritis
Citation: Knowles HJ (2017) Multiple Roles of Angiopoietin-Like 4 in Osteolytic Disease. Front. Endocrinol. 8:80. doi: 10.3389/fendo.2017.00080
Received: 23 February 2017; Accepted: 30 March 2017;
Published: 18 April 2017
Edited by:Xinhua Qu, Shanghai Ninth People’s Hospital, China
Reviewed by:Jennifer Tickner, University of Western Australia, Australia
Katherine A. Staines, Royal Veterinary College, UK
Copyright: © 2017 Knowles. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Helen J. Knowles, email@example.com