Bidirectional crosstalk between the bone extracellular matrix and lysosomes in bone remodeling and osteoporosis

Osteoporosis is a systemic skeletal disorder characterized by progressive loss of bone mass and deterioration of microarchitectural integrity. Traditionally, its pathogenesis has been attributed primarily to an imbalance in the number and activity of osteoblasts and osteoclasts. However, emerging evidence has uncovered a critical bidirectional interdependence between the integrity of the extracellular matrix (ECM) and the functional homeostasis of the intracellular lysosomal system—an axis increasingly recognized as the “bone matrix–lysosome crosstalk.” Despite its apparent importance, the central role of this regulatory circuitry in bone homeostasis and the mechanisms through which it becomes disrupted under pathological conditions remain insufficiently defined.This review synthesizes current advances regarding the cell type–specific functions of lysosomes across distinct bone cell populations and further examines how the ECM, as a dynamic microenvironment, exerts reciprocal control over lysosomal biogenesis and activity. We highlight how the biochemical composition and biophysical properties of the ECM govern lysosomal acidification, metabolic coupling, and degradative capacity with remarkable precision. During the progression of osteoporosis, structural compromise of the ECM and lysosomal dysfunction reinforce one another, establishing a self-amplifying pathological loop that accelerates the collapse of the bone microenvironment. Recognizing this reciprocal deterioration, we propose that restoring the dynamic equilibrium of the “ECM–lysosome axis” may represent a mechanistic pivot for reversing osteoporotic degeneration. Interventions targeting lysosomal function, reconstructing the bone ECM, and employing nanomedicine-enabled organelle-specific delivery hold particular promise for advancing precision therapeutics in osteoporosis.

1 Introduction

Osteoporosis (OP) is a systemic metabolic bone disorder characterized by reduced bone mass, degenerative alterations in bone microarchitecture, and increased skeletal fragility, fundamentally driven by a long-standing imbalance in bone remodeling that favors bone resorption (1, 2). With the rapid acceleration of global population aging, the societal burden of OP continues to escalate (3). Epidemiological data indicate that more than 200 million people worldwide are currently affected, with prevalence increasing particularly among postmenopausal women and elderly men. The resulting fragility fractures markedly elevate mortality and disability rates and impose substantial medical and economic burdens (2, 3). Although existing anti-resorptive and anabolic therapies can partially slow disease progression, they remain insufficient to fully restore the homeostasis of the bone microenvironment, suggesting that the core pathogenic mechanisms underlying OP are not yet completely understood (4, 5).

Bone tissue homeostasis relies on the integrity and dynamic remodeling of the extracellular matrix (ECM, 6). The bone ECM consists of highly organized collagen fibrils, non-collagenous proteins, proteoglycans, and mineralized hydroxyapatite crystals, which together provide mechanical support and a signaling and adhesion microenvironment that governs the survival, migration, and functional states of osteoblasts, osteoclasts, and osteocytes (6). Emerging research increasingly highlights that the ECM is not a static scaffold but an active signaling integrator within the bone microenvironment. Through alterations in mechanical cues, biochemical composition, and nanoscale topology, the ECM triggers metabolic reprogramming and fate decisions in bone cells (7). Consequently, any disturbances to the ECM—such as abnormal collagen crosslinking, heterogeneous mineralization, reduced elastic modulus, or nanoscale structural damage—may serve as early pathological drivers of OP.

Importantly, the maintenance of ECM integrity is not solely determined by its inherent structure but requires continuous renewal orchestrated by intracellular degradation and biosynthetic systems within bone cells (8–10). Central to this process is the lysosome (11). Traditionally viewed as the terminal degradative compartment responsible for breaking down proteins, lipids, and damaged organelles, the lysosome is now recognized as a pivotal regulatory hub integrating nutrient sensing, energy metabolism, autophagic flux, extracellular secretion, and inter-organelle communication (12–14). In bone metabolism, osteoblasts rely on lysosome-mediated trafficking of matrix vesicles and recycling of ECM components to sustain mineralization (15); osteoclasts depend on lysosome-driven acidification and protease release to execute bone resorption (16); and osteocytes utilize the lysosome–autophagy axis to maintain lacunar–canalicular patency and preserve responsiveness to microenvironmental signals (17).

With advances in understanding lysosomal function, accumulating evidence suggests that OP is not merely the consequence of imbalanced osteoblastic and osteoclastic activities but also reflects a bidirectional dysregulation between ECM integrity and lysosomal homeostasis (15–17). Weakening of the ECM alters mechanical loading and transmembrane adhesion cues, thereby impairing lysosomal biogenesis, acidification, and metabolic coupling with other organelles (18). Conversely, lysosomal dysfunction disrupts ECM renewal, causes imbalanced matrix degradation, and compromises bone cell survival, establishing a pathological positive feedback loop that progressively damages bone microarchitecture (19).

Given the profound interdependence between the ECM and the lysosome in sustaining bone homeostasis, establishing a conceptual framework of “ECM–lysosome crosstalk” provides a new lens through which to understand the pathogenesis of OP. This review aims to systematically elucidate how the ECM and lysosome reciprocally regulate each other’s structure and function within bone tissue, identify the critical points at which this axis becomes disrupted during OP progression, and explore therapeutic strategies targeting this regulatory network, with the goal of guiding future precision interventions for OP.

2 Lysosomal regulation of bone ECM homeostasis

2.1 Lysosomal function core

The lysosome, long regarded as the cell’s central degradative system, performs far more complex and proactive roles than a conventional “waste-processing compartment.” It functions as a multidimensional regulatory platform essential for maintaining the homeostasis of the bone extracellular matrix (ECM) (16, 20). Its activities rely on tightly coordinated molecular machinery and highly orchestrated cell biological processes (21).

A fundamental function of the lysosome is its ability to degrade ECM components through its acidic lumen and extensive repertoire of hydrolytic enzymes. Hydroxyapatite (HA), the principal inorganic constituent of the bone matrix, undergoes chemical dissolution within the extracellular acidic microenvironment generated by polarized osteoclasts (22). Upon polarization, lysosome-derived V-ATPase and the ClC-7 chloride channel are redistributed to the ruffled border of osteoclasts (22), where massive proton extrusion reduces the pH of the resorptive lacuna to approximately 4.5 (23). This highly acidic environment destabilizes the HA crystal lattice and dissociates it into Ca²⁺ and PO₄³^-, completing inorganic mineral dissolution (24). Thus, HA degradation is essentially a lysosome-equipped, proton-pump–driven extracellular acidolysis reaction rather than an intralysosomal enzymatic process.

Importantly, only after acid dissolution of HA are type I collagen fibrils exposed to the resorption lacuna (25). Type I collagen accounts for nearly 90% of the organic ECM (26). Once exposed extracellularly, lysosome-derived cathepsin K (CatK), a cysteine protease, forms a specific complex with chondroitin sulfate, which is crucial for its ability to cleave triple-helical collagen (27). CatK further degrades the triple helix and telopeptide regions, effectively dismantling collagen fibrils (27). Genetic and clinical studies demonstrate that mutations in TCIRG1 (encoding the a3 subunit of V-ATPase) or CLCN7 (encoding ClC-7) prevent lacunar acidification to levels required for HA dissolution (28, 29). Consequently, minerals remain intact, and collagen cannot be accessed or degraded by CatK or other lysosome-derived proteases (30). Clinically, this results in abnormally elevated bone density with brittle, poorly functional cortical bone (“dense but fragile”), narrowed marrow cavities, impaired hematopoiesis, and cranial nerve compression (31, 32). At the cellular level, osteoclasts are present in normal numbers but exhibit defective polarization and lysosomal trafficking, rather than decreased cell abundance (16, 33). Altogether, these findings highlight the indispensable role of the lysosome in degrading bone ECM.

The lysosome also serves as a central platform for nutrient sensing and metabolic reprogramming. Amino acids and small peptides produced during ECM degradation are hydrolyzed in the lysosomal lumen and transported to the cytosol, providing essential nitrogen and carbon sources for the resynthesis of collagen and non-collagenous matrix proteins (34). Accumulating evidence shows that mTORC1 is the key molecular switch linking lysosomal nutrient signals to ECM biosynthesis programs (35). Under amino acid sufficiency, Rag GTPases and the Ragulator complex recruit mTORC1 to the lysosomal surface, positioning it near Rheb for full activation (36). In contrast, during amino acid deprivation, GAP factors such as GATOR1 promote GDP-loading of RagA/B, weakening Rag–Ragulator anchoring and rapidly detaching mTORC1 from the lysosomal membrane, leading to its inactivation (37, 38). This reversible localization, controlled by Rag nucleotide states, has been validated through live-cell imaging, immunofluorescence colocalization, and functional perturbation in multiple mammalian cell types, including HEK293T and MEFs (39).

Within this lysosomal nutrient-sensing module, SLC38A9 acts as both a transporter and sensor of amino acids (35, 40). It transports leucine and other amino acids to the cytosol while simultaneously modulating Ragulator–Rag conformation, ensuring proper mTORC1 recruitment and activation (40). Conversely, knockdown or inhibition of SLC38A9 blunts mTORC1 responsiveness to amino acids and impairs its lysosome-dependent activation (35), suggesting that amino acids recycled from ECM degradation are essential for sustaining mTORC1-driven anabolic metabolism. Functionally, mTORC1 directly regulates ECM synthesis in bone cells (41). Inhibition of mTORC1 (e.g., via rapamycin) reduces type I collagen (COL1A1) expression and hydroxyproline deposition in vivo and in vitro (42), and similar findings have been reported in BMSCs where COL1A1 levels change in response to rapamycin-modified autophagy (43). These studies position mTORC1 as a crucial anabolic node that senses lysosome-derived nutrients and drives ECM regeneration.

The lysosome further regulates ECM quality control and turnover through multiple forms of autophagy. Macroautophagy removes damaged organelles and protein aggregates via fusion of autophagosomes with lysosomes (44). Under stress, BMSCs show increased autophagosome abundance and formation of autolysosomes as observed by electron microscopy (45). When lysosomal acidification and degradation are inhibited by chloroquine, the autophagy substrate p62 accumulates and ECM secretion becomes dysregulated (46, 47). In parallel, chaperone-mediated autophagy (CMA) selectively degrades intracellular proteins carrying KFERQ-like motifs, relying on the lysosomal membrane receptor LAMP2A for substrate translocation (48). Studies show that CMA activity declines with age, whereas restoration of LAMP2A partially rescues aged cell function (49, 50). In bone, Lamp2a-deficient mice exhibit reduced vertebral trabecular bone mass, impaired osteoblast mineralization, and altered osteoclast-supporting signals (51). CMA defects in other tissues cause accumulation of oxidized proteins and disrupt proteostasis (52), suggesting that CMA deficiency may indirectly promote ECM abnormalities and bone fragility.

Lysosomal biogenesis and global lysosomal function are governed by transcription factor EB (TFEB). Decreased nuclear TFEB levels have been reported in osteoporotic bone tissues (53). In osteoclasts, TFEB activity is regulated by the TSC2–mTORC1–TFEB axis, maintaining lysosomal capacity and cellular homeostasis under hypoxia (54). TFEB dysfunction impairs lysosomal degradation, blocks clearance of mineralized matrix, and disrupts ECM remodeling and cartilage-to-bone transition (54). Conversely, TFEB knockdown inhibits autophagic flux (abnormal LC3-II/LC3-I ratios and p62 accumulation) and reduces osteogenic markers such as ALP and OCN (19, 55–57). Together, these findings establish TFEB-driven lysosomal function as a central upstream regulator of bone formation and ECM homeostasis.

From substrate degradation to nutrient sensing and autophagy-mediated quality control, the lysosome operates through a highly coordinated, multifunctional network that exerts an active and indispensable role in maintaining the integrity and dynamics of the bone ECM (Figure 1).

Figure 1

Figure 1. Central roles of lysosomal function. The figure illustrates the central roles performed by lysosomes in bone tissue, encompassing three major domains. (I) Extracellular matrix (ECM) degradation: Osteoclasts traffic lysosomal membranes enriched in vacuolar-type H⁺-ATPase (V-ATPase) and chloride channel 7 (ClC-7) to the ruffled border. This machinery acidifies the resorption lacuna to dissolve hydroxyapatite (HA), while exposed type I collagen is subsequently degraded by Cathepsin K(Cat K). Deficiencies in T-cell immune regulator 1 (TCIRG1), encoding a subunit of V-ATPase, or chloride channel 7 gene (CLCN7) impair acidification and thereby abolish ECM degradation. (II) Nutrient sensing and ECM regeneration: Degradation products are further processed within lysosomes and contribute to tissue remodeling. Rapamycin-mediated inhibition of mechanistic target of rapamycin complex 1 (mTORC1) reduces collagen deposition. Solute carrier family 39 member 9 (SLC39A9) and GTPase-activating protein toward Rags 1 (GATOR1) regulate the recruitment of mTORC1 to the lysosomal membrane via the Ragulator–Ras-related GTP-binding protein (Rag) complex, enabling or preventing its activation by the Ras homolog enriched in brain (Rheb) GTPase, thereby influencing ECM synthesis. (III) Autophagy-mediated processes: Chloroquine-induced inhibition of lysosomal function leads to disordered ECM secretion. Lysosome-associated membrane protein 2A (LAMP2A)–dependent chaperone-mediated autophagy (CMA) eliminates damaged intracellular components, while the transcription factor EB (TFEB) axis orchestrates lysosomal biogenesis and autophagy. ECM, extracellular matrix; V-ATPase, vacuolar-type H⁺-ATPase; ClC-7, chloride channel 7; CLCN7, chloride channel 7 gene; HA, hydroxyapatite; CatK, Cathepsin K; TCIRG1, T-cell immune regulator 1; mTORC1, mechanistic target of rapamycin complex 1; SLC39A9, solute carrier family 39 member 9; GATOR1, GTPase-activating protein toward Rags 1; Rag, Ras-related GTP-binding protein; Ragulator, LAMTOR1–5 complex; Rheb, Ras homolog enriched in brain; CMA, chaperone-mediated autophagy; LAMP2A, lysosome-associated membrane protein 2A; TFEB, transcription factor EB.

2.2 Cell type-specific lysosomal regulation

Within the highly dynamic remodeling system of bone tissue, the dependence on lysosomal function varies substantially across different bone cell types. Although the lysosome is traditionally viewed as the intracellular degradative center, in the bone microenvironment it participates in far more diverse and specialized processes, including cell differentiation, ECM remodeling, initiation of mineralization, and intercellular communication. During the cyclical process of bone remodeling, osteoclasts, osteoblasts, and osteocytes respectively execute bone resorption, matrix production, and mechanosensation, and their lysosomal systems have therefore been “specialized” to accommodate distinct physiological demands. Such functional heterogeneity allows the lysosome to act not only as a degradative organelle but also as a critical signaling node in the bone remodeling network. Dissecting these cell-type–specific lysosomal regulatory modes is essential for understanding the fine-tuned mechanisms governing bone remodeling and the pathogenesis of osteoporosis.

In osteoclasts, the lysosomal system orchestrates a highly coordinated set of processes that enable efficient degradation of the bone ECM and constitute the core machinery of bone resorption. Upon attachment to mineralized bone surfaces, osteoclasts undergo pronounced cytoplasmic polarization, forming a ruffled border and a resorption lacuna that together create a sealed, highly acidified microenvironment known as the sealing zone (16). This microenvironment operates as an extracellular functional lysosome, formed through fusion of lysosomal vesicles with the bone-apposed plasma membrane (16). The acidic milieu is maintained by V-ATPase–driven proton pumping, which lowers the pH to levels suitable for mineral dissolution (23). Cathepsin K (CatK), one of the most critical lysosome-derived acidic proteases, specifically degrades collagen fibrils; its synthesis, activation, and targeted trafficking are precisely regulated to ensure effective ECM degradation (58). In Ctsk^-/^- mice, overall bone remodeling persists, yet osteoclast lysosomal compartments accumulate undigested collagen fragments and exhibit severely compromised collagenolytic capacity, confirming the indispensable role of CatK in physiological bone resorption (59). Lysosomes not only participate in extracellular matrix degradation but also exert essential regulatory functions during osteoclast formation. The fusion and incorporation of lysosome-derived carrier vesicles furnish the bone-resorbing membrane with the acidification machinery and hydrolytic enzymes required to dissolve mineralized bone and degrade its organic matrix (60). Recent studies further demonstrate that disruption of endocytic–lysosomal trafficking or blockade of the forward transport of secretory lysosomes markedly impairs precursor-cell fusion and compromises osteoclast formation, underscoring the pivotal role of lysosome-dependent vesicular dynamics in driving osteoclastogenesis (61). Additionally, the RANKL pathway—a master regulator of osteoclast differentiation—directly modulates lysosomal enzyme expression, V-ATPase activity, and its subunit distribution via transcription factors such as NFATc1. These regulations exhibit clear stage- and dose-dependent patterns, indicating that lysosomal activity is dynamically tuned in response to remodeling demands rather than constitutively active (62). Disruption of lysosomal function leads to aberrant bone resorption—either excessive or insufficient—thereby destabilizing the balance between bone formation and resorption and predisposing to osteoporosis or osteosclerosis. Defining the spatial distribution, secretion dynamics, and regulatory networks of the osteoclast lysosome is therefore central to elucidating bone remodeling mechanisms and developing innovative anti-osteoporotic strategies.

Compared with the well-characterized role of the lysosome in osteoclast-mediated ECM degradation, recent studies have highlighted the importance of lysosomal regulation in osteoblasts and osteocytes for matrix synthesis, mineralization, and tissue homeostasis. During matrix mineralization, the lysosome performs functions that extend beyond classical degradation. Using nanoscale imaging, Iwayama et al. (63) demonstrated that mineralizing osteoblasts generate mineralizing vesicles (MVs), which accumulate within multivesicular bodies (MVBs) and undergo lysosome-dependent processing before extracellular release. These MVs contain amorphous calcium phosphate (ACP), deposit between collagen fibrils, and act as nucleation sites for mineral initiation. Pharmacological inhibition of lysosomal acidification or exocytosis markedly reduces MV secretion and mineral nodule formation, underscoring the indispensable role of the lysosome in initiating mineralization (63). In ECM synthesis, lysosomes regulate vesicle maturation, trafficking, and exocytosis, which are essential for the secretion of type I collagen and other ECM constituents (64). The autophagy–lysosome system in osteoblasts further maintains organelle quality control and supports differentiation. Dysregulated autophagy–lysosome activity impairs ECM production and disrupts mineralization rhythms, ultimately compromising bone-forming capacity (65, 66). Selective autophagy—particularly mitophagy—is crucial for long-term osteoblast function. Deficiency in Parkin-mediated mitophagy promotes accumulation of reactive oxygen species (ROS), accelerates osteoblast senescence, and markedly reduces matrix deposition (66), linking lysosomal quality-control pathways to age-related bone loss.

Osteocytes, which constitute 90–95% of all bone cells, reside deep within the lacuno–canalicular system (LCS), an extensive network of lacunae and canaliculi that allows intercellular connectivity and mechanotransduction (66). This unique architecture enables osteocytes to function as central orchestrators of mechanical sensing, ECM turnover, and mineral homeostasis (67). Accumulating evidence shows that the ECM-regulating capacity of osteocytes relies heavily on the lysosome–autophagy axis (68). As “microenvironmental custodians,” osteocytes perform perilacunar/canalicular remodeling (PLR) to maintain LCS morphology and patency (69). This process requires lysosomal storage and secretion of hydrolytic enzymes, including CatK (69). Conditional knockout studies demonstrate that suppression of osteocyte-derived CatK blocks lactation-associated PLR and prevents bone loss (70), indicating that osteocytes actively remodel ECM rather than relying solely on osteoclasts. Autophagy–lysosome pathways are equally essential for osteocyte quality control and ECM homeostasis. Basal autophagy clears damaged mitochondria and protein aggregates, sustaining osteocyte metabolic fitness and mechanosensitivity (17). Impaired autophagic flux or abnormal lysosomal acidification causes rapid cellular injury, apoptosis, and functional decline. Mechanical loading induces autophagy-dependent RANKL secretion from osteocytes, promoting osteoclastogenesis and facilitating matrix removal (71), linking osteocyte health directly to bone structural integrity. Furthermore, the lysosome–endosome system regulates the biogenesis and secretion of extracellular vesicles (EVs) and matrix vesicles, whose cargoes—proteases, miRNAs, and signaling peptides—dynamically modulate ECM synthesis and resorption in neighboring osteoblasts, osteoclasts, and BMSCs (72). These findings position osteocyte lysosomal function as a pivotal hub that integrates inward degradative processes with outward signaling cues, thereby maintaining bone quality and resilience. Dysfunction of the lysosome or autophagy in osteocytes simultaneously disrupts intracellular homeostasis and ECM-directed communication, leading to LCS deterioration, excessive pro-resorptive signaling, and ultimately compromised bone strength. Thus, the osteocyte lysosome–autophagy axis represents a promising but underexplored therapeutic target beyond traditional osteoclast- and osteoblast-centered strategies.

In summary, from osteoclast-dependent lysosome-driven bone resorption, to osteoblasts utilizing lysosomes for matrix transport and mineralization initiation, to osteocytes employing the lysosome-autophagy axis to maintain lacuno-canalicular system integrity and regulate intercellular signaling, the role of lysosomes in distinct bone cells extends far beyond that of a traditional intracellular degradation organ. Instead, it exhibits a highly cell-type-specific functional landscape. These distinctions not only govern the rhythm and efficiency of bone remodeling but also constitute the key molecular basis for diseases such as osteoporosis. Future in-depth analysis of lysosomal distribution patterns, dynamic regulation, and their upstream signaling networks within distinct bone cells will offer novel perspectives on cross-cellular regulation of bone remodeling. This research will also provide crucial theoretical foundations for developing precision therapeutic strategies targeting lysosomal function (Table 1).

Table 1

Table 1. Cell–type–specific lysosomal regulation in bone remodeling.

3 Bone ECM affects the realization of lysosomal function

3.1 Chemical microenvironment of the bone matrix: a multidimensional regulatory network governing lysosomal biogenesis

The chemical microenvironment of the bone matrix is far more than a static structural scaffold. Rather, it constitutes a dynamic, multidimensional signaling system composed of structural components (minerals, collagen), instructive biochemical signals (growth factors, cytokines), regulatory cues (enzymes, pH), and energy and metabolic inputs (73–76). By integrating these biochemical dimensions, the bone matrix provides precise guidance for lysosomal biogenesis and function, positioning itself as a central orchestrator of bone remodeling.

The structural components of the matrix—primarily inorganic minerals and organic substrates—define the initial physicochemical landscape in which lysosomes operate (77). Inorganic minerals are predominantly arranged as hydroxyapatite crystals, conferring mechanical strength to the skeleton (78). During bone resorption, osteoclasts generate a sealed zone and ruffled border (16), where V-ATPase localizes to the ruffled border membrane to pump protons outward, thereby dissolving hydroxyapatite and releasing calcium and phosphate (79, 80). Elevated extracellular Ca²⁺ can bind the lysosomal membrane channel TRPML1 and enhance membrane permeability, triggering Ca²⁺ efflux and activating the calcineurin–TFEB axis (81). Lysosomal biogenesis is centrally regulated by TFEB, whose nuclear activation state dictates the transcriptional program and functional maturation of the lysosomal network (82). Conversely, high phosphate concentrations—especially in the form of calcium–phosphate complexes (CPPs)—can be internalized and accumulate within late endosomes/lysosomes, neutralizing luminal acidity, inhibiting hydrolase activity, and impairing matrix-fragment degradation (83–85).

Collagen type I, which constitutes over 90% of the organic matrix, not only provides a scaffold for mineral deposition but also shapes lysosomal signaling through its degradation fragments. These fragments activate integrin α2β1 and stimulate downstream FAK/mTORC1 signaling, thereby relieving TFEB cytoplasmic retention and promoting its nuclear entry (36, 86, 87). Through these mechanisms, structural components of the matrix directly set the biochemical “background” for lysosomal activity.

Embedded within the matrix, bioactive molecules form an additional regulatory layer that translates matrix degradation signals into precise instructions for lysosomal remodeling. Growth factors such as BMPs and TGF-β are stored in a latent state bound to matrix proteins including osteopontin and fibronectin. They are activated during osteoclast-mediated acidification and matrix dissolution (74, 88). Activated TGF-β triggers intracellular Ca²⁺ elevation and stimulates the calmodulin–calcineurin axis, promoting dephosphorylation and nuclear translocation of TFEB/TFE3 and enhancing transcription of lysosomal and autophagy-related genes (89, 90). Likewise, BMP2 activates the BMPR–TAK1 pathway, which may cooperate with the TAB/RCAN complex to fine-tune calcineurin activity and further amplify TFEB-driven lysosomal biogenesis and acidification (91).

Cytokines secreted by bone matrix–embedded cells constitute yet another tier of regulation. RANKL binds the receptor RANK on osteoclast precursors, recruits TRAF6, and activates NF-κB and MAPK signaling, ultimately inducing the expression and nuclear localization of the master transcription factor NFATc1 (92, 93). NFATc1 binds promoters of lysosomal genes—including cathepsin K, LAMP2, and V-ATPase subunits—constructing the lysosomal apparatus required for efficient bone resorption (16, 62). In addition, RANKL activates PKCβ-dependent phosphorylation pathways that enhance TFEB activation, driving lysosomal maturation during osteoclast differentiation (94). Loss of TFEB or PKCβ suppresses lysosomal gene expression and increases bone mass, underscoring the essential role of the RANKL–PKCβ–TFEB axis in controlling lysosomal biogenesis and bone resorption (94). Conversely, osteoblast-derived OPG competitively binds RANKL and attenuates NFATc1-mediated lysosomal remodeling (93).

The enzymatic milieu and pH gradients created within the bone matrix function as rapid and direct regulatory tools that modulate lysosomal activity and membrane stability. Acidification at the osteoclast ruffled border reflects a dynamic equilibrium constrained by matrix chemistry rather than a unidirectional proton-pumping process (16, 79, 95). V-ATPase-driven proton extrusion dissolves hydroxyapatite, releasing Ca²⁺ and PO₄³^-, which in turn modify extracellular ionic strength and buffer capacity, thereby influencing lysosomal membrane electrochemical stability and fusion/exocytosis efficiency (16, 96). The stability of lysosomal membranes requires a sustained proton gradient and correct folding/glycosylation of membrane proteins such as LAMP1, LAMP2, and H⁺-dependent chaperones (97, 98). Disruption of luminal acidification leads to lysosomal membrane permeabilization (LMP), leakage of cathepsins B/D, and downstream stress responses (99–101). Thus, the pH microenvironment defined by the matrix not only determines catalytic efficiency but also regulates lysosomal membrane integrity and secretory rhythm. This matrix–lysosome interplay reveals new molecular foundations for pathological bone resorption and identifies potential therapeutic windows targeting pH-lysosome homeostasis.

Lysosomal biogenesis, membrane trafficking, and maintenance of luminal acidity are energy-demanding processes. The chemical microenvironment of the matrix provides critical metabolic support by reshaping cellular metabolic programs and energy signaling pathways (75, 102, 103). Bone matrix cells—particularly osteoblasts and osteoclasts—dynamically adjust metabolic preferences in response to local oxygen tension, ionic composition, and lactate levels (7, 104). Hypoxia in remodeling or repair sites stabilizes HIF-1α, shifting metabolism from oxidative phosphorylation toward glycolysis to sustain ATP production under low O₂ (105). Glycolytic ATP supports energy-intensive systems such as V-ATPase and lysosomal transport machinery and also regulates TFEB nuclear translocation via the AMPK–mTORC1 axis, thereby promoting lysosomal biogenesis and autophagic flux (106–108). Glycolytic by-products, including lactate and associated protons, help maintain local pH conditions favorable for lysosomal enzyme activity (109). Moreover, the skeleton acts as an endocrine organ; osteocalcin (OCN) enhances systemic metabolic efficiency by stimulating insulin signaling in β-cells and skeletal muscle, indirectly supporting the metabolic demands of osteoblasts (110). Through this integration of local and systemic metabolic cues, the matrix microenvironment serves not only as a reaction field for lysosomal activity but also as a metabolic power source.

Collectively, the chemical microenvironment of the bone matrix forms a multilayered, dynamic regulatory network that integrates structural cues, biochemical signals, regulatory tools, and metabolic inputs to orchestrate lysosomal biogenesis and functional output. Future research should employ advanced platforms—such as real-time single-organelle imaging and biomimetic matrix systems—to delineate the dynamic interactions among these dimensions under physiological and pathological conditions. These insights are expected to uncover precise molecular targets and innovative therapeutic strategies aimed at modulating lysosomal function to treat osteoporosis and other skeletal disorders. (Figure 2).

Figure 2

Figure 2. Bone matrix microenvironment: a multidimensional regulatory network governing lysosomal biogenesis the schematic illustrates how the structural components of the bone matrix, the acidic microenvironment, signaling networks, and energy–metabolic cues collectively regulate lysosomal activity and transcription factor EB (TFEB)–dependent lysosomal biogenesis (1). Structural components:Hydroxyapatite dissolution releases calcium ions (Ca²⁺) and phosphate ions (PO₄³^-), which activate Ca²⁺ signaling through transient receptor potential mucolipin 1 (TRPML1) and promote the nuclear translocation of TFEB. Phosphate ions and calcium phosphate particles (CPPs) elevate lysosomal pH and suppress lysosomal hydrolase activity. Type I collagen regulates TFEB through the α2β1 integrin–focal adhesion kinase (FAK)–mechanistic target of rapamycin complex 1 (mTORC1) axis. (2) Acidification and pH regulation:Vacuolar-type H⁺-ATPase (V-ATPase) maintains lysosomal acidity, facilitates hydroxyapatite dissolution, and establishes a Ca²⁺/PO₄³^- feedback loop. Elevation of lysosomal pH leads to membrane destabilization and lysosomal membrane permeabilization (LMP), resulting in the leakage of Cathepsins into the cytosol. (3) Signaling networks:Transforming growth factor-β (TGF-β) and bone morphogenetic protein 2 (BMP2) activate TFEB via the Ca²⁺–calcineurin pathway. Receptor activator of nuclear factor-κB ligand (RANKL)–nuclear factor of activated T cells 1 (NFATc1) signaling upregulates lysosomal and osteoclastic genes, whereas osteoprotegerin (OPG) exerts inhibitory effects. (4) Energy and metabolic cues:Hypoxia–hypoxia-inducible factor 1α (HIF-1α) enhances glycolysis and adenosine triphosphate (ATP) supply to support V-ATPase activity. Lactate and protons (H⁺) help maintain lysosomal acidity. Osteocalcin (OCN) links systemic energy metabolism to lysosomal function in bone cells. ATP, adenosine triphosphate; BMP2, bone morphogenetic protein-2; Ca²⁺, calcium ion; CPPs, calcium phosphate particles; FAK, focal adhesion kinase; H⁺, proton; HIF-1α, hypoxia-inducible factor-1α; LMP, lysosomal membrane permeabilization; mTORC1, mechanistic target of rapamycin complex-1; NFATc1, nuclear factor of activated T cells 1; OCN, osteocalcin; OPG, osteoprotegerin; PO₄³^-, phosphate ion; RANKL, receptor activator of nuclear factor-κB ligand; TGF-β, transforming growth factor-β; TFEB, transcription factor EB; TRPML1, transient receptor potential mucolipin-1; V-ATPase, vacuolar-type H⁺-ATPase.

3.2 Mechanistic regulation of lysosomal function by the physical properties of the extracellular matrix

The physical attributes of the extracellular matrix (ECM) constitute a critical regulatory dimension for lysosomal function, complementing the chemical signaling framework described above. Emerging evidence indicates that ECM stiffness, topographical organization, and piezoelectric properties profoundly influence lysosomal biogenesis, spatial distribution, trafficking dynamics, and degradative capacity through mechanotransduction, cytoskeletal remodeling, and nanoscale force responsiveness. These insights establish a new conceptual foundation for understanding skeletal homeostasis and the pathological mechanisms underlying osteoporosis.

YAP/TAZ act as core mechanosensitive transcriptional regulators within the bone microenvironment, with their phosphorylation status and nuclear localization directly responding to ECM stiffness. At the cellular level, stiff substrates are sensed via integrin–focal adhesion (FA) complexes, where integrin clustering and FA maturation activate the FAK/Src–RhoA/ROCK cascade, promoting actin stress fiber assembly and establishing a robust intracellular tension network (10, 111, 112). This structural–mechanical coupling enables efficient transmission of rigidity cues to YAP/TAZ activation. Under stiff ECM conditions, YAP/TAZ undergo dephosphorylation and nuclear translocation (103, 113), where they interact with TFE3 or TFEB to form transcriptional complexes that initiate lysosomal and autophagy-related gene expression (114). Nuclear YAP/TAZ activation further modulates mTORC1 assembly and activity at the lysosomal membrane, thereby regulating lysosomal acidification and proteolytic efficiency (115, 116).

Mechanotransduction also induces metabolic reprogramming. Upon YAP/TAZ activation, mesenchymal stem cells exhibit enhanced glycolysis and mitochondrial oxidative phosphorylation, resulting in elevated ATP production that fuels V-ATPase-dependent proton pumping in lysosomes (103, 106). Concurrently, mechanical stimulation leads to the accumulation of metabolites such as succinate and lactate (117, 118), which function not only as metabolic intermediates but also as epigenetic regulators of lysosome-related transcription factors (119, 120). For example, succinate inhibits the demethylase FTO, increasing m6A modification of osteogenic regulators such as Runx2 and promoting coordinated activation of osteogenic gene expression and lysosomal function (15, 121, 122). Collectively, ECM stiffness engages YAP/TAZ as central mechanosensors to orchestrate a hierarchical regulatory cascade—ranging from cytoskeletal remodeling to metabolic control—that links mechanical inputs to lysosomal function. This mechanotransduction–transcription–metabolism axis reveals a multilayered framework through which the bone microenvironment regulates intracellular degradative systems and maintains skeletal homeostasis.

The ECM also possesses hierarchical topographical features, with collagen fibrils exhibiting a periodic banding pattern (~67 nm) and intertwining with hydroxyapatite crystals in defined orientations to form a highly organized composite structure (123). These topographical attributes serve not only as structural scaffolds but also as regulatory platforms for organelle function (124), particularly during lysosome-dependent matrix remodeling. Cells detect and interpret ECM topography via integrin–FA complexes, transmitting these cues to the RhoA/ROCK axis to modulate cytoskeletal tension (125–127). Variations in collagen alignment and microdomain stiffness reshape FAK-mediated mechanotransduction, altering microtubule stability and actin filament dynamics (128, 129). This spatial reorganization of cytoskeletal tension influences lysosomal transport along microtubules, affecting their subcellular distribution and interactions with mitochondria, which are critical for energy and signaling homeostasis (130, 131).

Recent advances in multiscale organelle mechanobiology demonstrate that lysosomal motility, mitochondria–lysosome contact frequency, and membrane fusion probability are highly sensitive to external mechanical inputs. On stiff or highly aligned substrates, increased cytoskeletal tension and traction forces promote lysosomal clustering near FA-rich regions and the cell periphery, facilitating mechanically coupled functions such as membrane fusion and exocytosis (131, 132). In contrast, soft or topographically disordered ECM leads to more diffuse lysosomal distribution and a higher prevalence of mitochondria-associated lysosomal subpopulations (131), altering lysosomal activity (133, 134). This form of “spatial reprogramming” underscores the mechanosensitivity of lysosomes and highlights ECM topology as a determinant of local enzymatic release and degradative precision.

The piezoelectric properties of the ECM create a unique mechano-electrical coupling interface that links physical stimuli to cellular metabolic and signaling responses (135–137), offering a non-chemical mechanism for shaping lysosomal function. As a natural electromechanical converter, collagen generates piezoelectric dipoles upon mechanical deformation, which can drive hydroxyapatite nucleation even in the absence of osteoblasts (138). Conversely, hydroxyapatite enhances the mechanical responsiveness of collagen fibrils through structural reinforcement, promoting alignment of piezoelectric domains and amplifying overall piezoelectric output (139). Mechanical loading or physiological body movement can induce localized electrical potentials within bone tissue or engineered piezoelectric substrates, selectively activating mechanosensitive ion channels such as Piezo1 and triggering rapid intracellular Ca²⁺ transients on the millisecond–second scale (140, 141). These Ca²⁺ signals activate the calcineurin–TFEB pathway, thereby influencing lysosomal biogenesis (81).

In summary, the physical properties of the ECM constitute a multidimensional regulatory network that governs lysosomal function. These insights not only deepen the current understanding of bone biology but also provide a theoretical basis for developing therapeutic strategies that target the physical microenvironment. Future research should focus on elucidating how diverse physical cues are integrated into unified cellular responses and on designing intelligent biomaterials capable of dynamically guiding bone regeneration, thereby opening new avenues for the prevention and treatment of osteoporosis and related skeletal disorders (Figure 3).

Figure 3

Figure 3. Regulatory mechanisms by which extracellular matrix (ECM) physical properties govern lysosomal function this figure illustrates how three key physical attributes of the bone extracellular matrix—stiffness, extension structure, and piezoelectric property—integrate to regulate lysosomal positioning, acidification, and transcription factor EB (TFEB)–dependent lysosomal biogenesis. (A) Matrix stiffness.Sensing of matrix stiffness activates integrin–focal adhesion (FA) complexes, which in turn stimulate focal adhesion kinase (FAK)/Src and RhoA/Rho-associated kinase (ROCK) signaling, promoting the formation of actin stress fibers. These events drive the dephosphorylation and coordinated nuclear translocation of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) together with transcription factor E3 (TFE3)/TFEB. Downstream effects include modulation of mechanistic target of rapamycin complex 1 (mTORC1), enhancement of lysosomal acidification capacity, increased protease activity, metabolic reprogramming (including lactate and succinate production), and upregulation of autophagy-related gene expression. (B) Extension structure of the ECM. The spatial extension architecture of the ECM influences lysosomal distribution. High-stiffness or highly ordered collagen–hydroxyapatite composite structures strengthen integrin clustering and focal adhesion remodeling, facilitating lysosomal accumulation along cytoskeletal traction pathways. In contrast, low-stiffness or disordered ECM structures cause lysosomal dispersion and disrupt coordinated mitochondrial metabolism. (C) Piezoelectric properties of the bone matrix. The piezoelectric effect of bone arises from periodic mechanical loading on collagen fibrils, generating dipole signals. Piezo-type mechanosensitive ion channel component 1 (Piezo1) senses mechanically induced or movement-driven calcium ion (Ca²⁺) influx, activating the calcineurin–TFEB pathway and promoting lysosomal biogenesis. Hydroxyapatite deposition further amplifies the piezoelectric response, establishing a positive feedback loop linking ECM, Ca²⁺ signaling, and lysosomal function. ECM, extracellular matrix; FA, focal adhesion; FAK, focal adhesion kinase; Src, proto-oncogene tyrosine-protein kinase Src; RhoA, Ras homolog family member A; ROCK, Rho-associated kinase; YAP, Yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif; TFE3, transcription factor E3; TFEB, transcription factor EB; mTORC1, mechanistic target of rapamycin complex 1; Piezo1, Piezo-type mechanosensitive ion channel component 1; Ca²⁺, calcium ion; HA, hydroxyapatite; lactate, lactic acid; succinate, TCA-cycle intermediate.

4 The interaction mechanism between lysosomes and bone ECM in osteoporosis

4.1 Mechanisms underlying bone resorption

Aberrantly enhanced bone resorption is a fundamental pathological basis of osteoporosis, driven primarily by dysregulation of how osteoclast lysosomal systems recognize bone ECM, direct polarized secretion, and re-internalize and process degradation products (16). Among these processes, cathepsin K (CatK; encoded by CTSK) is the pivotal collagenolytic enzyme within lysosomes and serves as a decisive determinant of bone resorption. Cellular studies demonstrate that maximal inhibition of CatK completely blocks the osteoclast transition from pit-type to trench-type resorption, markedly reducing trench-like erosion while increasing pit-like corroded areas. These findings indicate that CatK activity directly shapes osteoclast selectivity toward distinct ECM structural types (142). In estrogen-deficient mouse models, delayed trabecular mineralization, disorganized collagen fibrils, and heightened osteoclast activity coincide with pronounced CTSK upregulation, supporting the notion that hyperactivated lysosomal proteolysis is a key driver of ECM degradation in osteoporosis (143). Conversely, CTSK knockout results in increased trabecular number and thickness, denser microarchitecture, and a significant elevation in bone volume fraction (BV/TV), representing a typical phenotype of impaired bone resorption and secondary bone mass accumulation (144). However, despite greater stiffness and strength, Ctsk^-/^- bone exhibits reduced deflection prior to fracture, displaying a “stiffer-but-more-brittle” mechanical profile. This suggests that the absence of CatK-mediated organic matrix remodeling compromises energy absorption and elasticity in bone tissue (144).

Clinical studies further reinforce the centrality of CatK in bone resorption control. The CatK inhibitor odanacatib significantly reduces biochemical markers of bone resorption and increases bone mineral density (145, 146), with its efficacy closely correlated with reduced CatK activity (147, 148). CatK is also persistently upregulated in osteoarthritic tissues (149). Other inhibitors, such as ONO-5334, exhibit sustained suppression of bone resorption (150, 151). Nevertheless, several CatK inhibitors failed to reach clinical application owing to cardiovascular and dermatologic adverse events observed in trials (148). Collectively, these findings establish CatK as the terminal effector molecule of osteoclast lysosomal ECM degradation, and its aberrant activation as a prominent hallmark of excessive bone resorption and osteoporosis progression.

Beyond enzymatic degradation, lysosomal membrane trafficking and localization mechanisms are equally essential in governing ECM breakdown. The membrane trafficking protein RUFY4, via its RUN and FYVE domains, mediates protein–membrane interactions and directs lysosomal transport along microtubules to the osteoclast ruffled border, thereby coordinating lysosomal positioning, fusion, and cargo release (152). Recent work identifies RUFY4 as a critical regulatory hub in bone resorption: its expression is induced by the RANKL–NF-κB p65–NFATc1 pathway, and RUFY4 deficiency leads to decoupling of the Rab7–LAMP2 complex, reduced acidic lysosome abundance, diminished CatK secretion, impaired collagen degradation, and increased bone density accompanied by defective remodeling (20). Thus, RUFY4 acts as a molecular axis coupling ECM-derived cues to lysosomal trafficking, indispensable for osteoclast resorptive function.

From the perspective of membrane-domain construction, SNX10-mediated vesicular trafficking also plays an essential role in bone resorption. Evidence indicates that SNX10 controls the formation and transport of distinct membrane compartments, maintaining the integrity of the osteoclast plasma membrane–ruffled border axis (153). Various autosomal recessive osteopetrosis (ARO) models resulting from SNX10, TCIRG1, or CLCN7 mutations consistently exhibit defective ruffled border formation and impaired acidification capacity in osteoclasts, demonstrating that despite differing molecular roles, these genes converge functionally to disrupt the ruffled-border-centered “acidification–secretion” system critical for ECM degradation (23, 79, 154, 155). Convergent findings from human genetics, animal models, and cellular studies related to the SNX10 (R51Q) mutation firmly establish SNX10 as a key node required for lysosomal membrane functions during osteoclast-mediated resorption.

Histological evidence from human osteopetrosis further highlights the distinct contributions of lysosomal function to normal ECM mineralization. In patients harboring TCIRG1 mutations, undecalcified iliac crest biopsies consistently reveal abundant osteoid accumulation and significantly reduced mineralization, indicating that defects in the lysosomal H⁺-ATPase subunit impair lysosomal acidification and directly induce osteomalacia (156). In contrast, patients with CLCN7 or TNFRSF11A mutations exhibit impaired bone resorption but preserved ECM mineralization, suggesting that lysosomal acidification and lysosomal ion homeostasis represent separable regulatory modules of ECM processing (156). This distinction demonstrates that adequate lysosomal acidification is indispensable for proper mineralization cycles, whereas ion flux regulation primarily affects the efficiency of bone resorption rather than mineralization itself.

Clinical evidence from lysosomal storage disorders also supports the central role of lysosome–matrix interactions in skeletal homeostasis. In mucopolysaccharidosis type I H (MPSIH), deficiency of IDUA leads to lysosomal and extralysosomal accumulation of glycosaminoglycans (GAGs) in osteoblasts and other cells, disturbing ECM metabolism and connective tissue integrity (157). Gene therapy restoring IDUA activity effectively clears systemic and skeletal GAG storage, improves joint stiffness, promotes near-normal bone growth, and stabilizes spinal architecture, demonstrating that recovering lysosomal function can re-establish the ECM-associated microenvironment and restore bone remodeling dynamics (157).

In summary, the lysosomal system exerts multidimensional control over ECM degradation, mineralization, and biomechanical performance through its enzymatic activity, acidification capacity, ion homeostasis, membrane trafficking, and metabolic load under pathological conditions. Its interplay with the ECM forms the core molecular network governing bone resorption. Even subtle perturbations in lysosomal function are sufficient to induce imbalanced resorption, aberrant matrix degradation, or mineralization defects, collectively driving the onset and progression of osteoporosis. Therefore, molecular targets along the lysosome–matrix interaction axis—such as CatK, RUFY4, and SNX10-associated trafficking machinery—represent promising strategies for precision intervention to normalize bone resorption and improve skeletal structural quality (Table 2).

Table 2

Table 2. Interaction mechanisms between lysosomes and bone ECM in osteoporosis.

4.2 Mechanisms underlying bone formation

The homeostasis of bone formation depends on the precise interplay between the ECM and the lysosomal system within osteogenic cells, an interaction that becomes markedly disrupted in osteoporosis. Recent studies position lysosomes as a central lysosomal signaling hub, integrating extracellular matrix cues with intracellular differentiation programs (158). Under osteoporotic conditions, alterations in ECM composition and mechanics, together with defects in lysosomal trafficking, acidification, and degradative efficiency, destabilize this regulatory axis and ultimately diminish osteogenic output (15).

As a biochemical and biomechanical information reservoir, the ECM modulates lysosomal behavior through integrin-dependent adhesion signaling, mechanotransduction, and matrix remodeling dynamics (170, 171). In osteoporosis, reduced matrix mineralization, disorganized collagen networks, and nanoscale structural deterioration impair osteoblast mechanosensitivity and disrupt lysosomal positioning, acidification, and autophagy–lysosome flux (131, 159, 160). For instance, TMEM175 deficiency in BMSCs leads to insufficient lysosomal acidification, compromising ECM signal responsiveness and resulting in pronounced defects in osteogenic differentiation (15). These findings demonstrate that pathological ECM remodeling can reprogram lysosomal biogenesis and function, thereby altering cellular metabolism and lineage commitment.

Lysosomes act as key executors of the osteogenic program by regulating autophagic flux, mitochondrial homeostasis, and organelle quality control (1). Beyond their canonical degradative role, lysosomes also function as metabolic and signaling transducers. Biomimetic citrate–zinc–HA nanoparticles internalized by BMSCs are selectively delivered into lysosomal compartments, where they enhance WNT activity, increase ALP expression, and promote ECM mineralization—highlighting lysosomal participation in translating inorganic microenvironmental cues into osteogenic signals (163). Similarly, DHAP undergoes lysosomal degradation to release PO₄³^-, driving local ATP production and activating the adenosine–cAMP/PKA–Runx2 cascade, further supporting the unique role of lysosomes in converting mineral inputs into bioenergetic and transcriptional outputs (161).

Structural disruption of the endolysosomal pathway has also emerged as a major driver of osteoblast senescence and functional exhaustion. Loss of CHMP5 perturbs endolysosomal trafficking and degradation, reduces VPS4A abundance, induces mitochondrial dysfunction, and promotes excessive ROS accumulation, collectively accelerating osteoblast senescence. Senescent cells not only lose osteogenic capacity but also impair the local bone microenvironment through paracrine signaling. Notably, senolytic clearance effectively reverses CHMP5-deficiency–associated defects in bone formation, underscoring the therapeutic potential of targeting the lysosome–senescence axis (162).

Together, ECM deterioration and lysosomal dysfunction establish a mutually reinforcing pathological loop. ECM mechanical weakening and compositional degradation suppress lysosomal activity, whereas lysosomal defects further disrupt ECM synthesis and mineralization, driving persistent declines in bone formation. Deeper mechanistic layers include the breakdown of ECM–integrin–lysosome positioning circuits, insufficient metabolic output from the autophagy–mitochondria axis, and ESCRT-dependent endolysosomal trafficking imbalances that promote cellular senescence. Disruption of this bidirectional ECM–lysosome communication constitutes a core pathogenic mechanism underlying osteoporotic bone loss (Table 2).

4.3 Dysregulation of osteocytes homeostasis

Osteocytes are the terminally differentiated cells of the osteoblastic lineage and represent the most abundant and long-lived cell population within bone tissue (9). Owing to their residence in a microenvironment characterized by hypoxia, nutrient limitation, and continuous mechanical loading, osteocytes are highly dependent on lysosome-mediated autophagy. This dependence not only ensures their survival and metabolic homeostasis but also directly shapes the quality and mechanical integrity of the bone matrix (168, 169). Osteocytes in mouse and human cortical bone display punctate LC3 localization, indicating that a basal level of autophagy is essential for sustaining osteocyte viability under nutrient deprivation or hypoxic stress (164). Beyond maintaining homeostasis under physiological conditions, osteocyte autophagy plays a crucial role in mediating endocrine and pharmacologic modulation of bone metabolism. Glucocorticoid (GC) exposure induces autophagosome accumulation and upregulates LC3A/LC3B, ATG2, ATG7, and other key components, reflecting robust activation of the lysosome-dependent autophagy pathway (165). This effect is dose-dependent—low-dose GC-induced autophagy enhances antioxidant defenses and confers partial protection to bone, whereas high doses suppress antioxidant gene expression, impair autophagosome–lysosome fusion and degradation, and ultimately trigger cellular stress, functional decline, and accelerated bone loss (166).

The dependence of osteocytes on lysosomal function is also evident in their intimate interaction with the bone matrix. Once lysosome–autophagy activity becomes impaired, osteocytes exhibit synchronized defects in matrix sensing, signal transmission, and survival, constituting an early pathogenic event in osteoporosis (1, 167). Under specific physiological stresses such as lactation, elevated calcium demand drives osteocytes to activate local perilacunar remodeling and upregulate bone-resorptive genes including CTSK (70). Genetic studies reveal that osteocyte-specific Ctsk deletion markedly suppresses lactation-induced expansion of perilacunar cavities, reduces osteoclast recruitment, and prevents deterioration of trabecular microarchitecture. Moreover, this manipulation stabilizes systemic calcium homeostasis by modulating PTH, PTHrP, and 1,25(OH)₂D levels, thereby maintaining calcium content in both maternal serum and milk (70). These findings highlight that the osteocytic lysosomal system, beyond supporting intrinsic homeostasis, participates in local matrix degradation and systemic calcium regulation during complex physiological adaptations.

Collectively, the lysosome–autophagy axis that maintains osteocyte homeostasis occupies a central role in osteoporosis. As cells positioned at the intersection of skeletal structure, mechanoadaptation, and metabolic regulation, osteocytes translate lysosomal dysfunction into multilevel disturbances that cumulatively drive bone deterioration. Conceptualizing the lysosome–matrix interface as a key pathogenic node not only deepens our understanding of the systemic nature of osteoporosis but also provides a new therapeutic framework for targeting osteocyte autophagy and lysosomal function in future interventions (Table 2).

5 Intervention strategy targeting the ECM-lysosomal axis

5.1 Restoring and enhancing lysosomal function: organelle-targeted therapeutic interventions

Restoring lysosomal function is fundamental for sustaining ECM turnover and skeletal homeostasis (16), positioning reinforcement of the “ECM–lysosome axis” as a central therapeutic direction. As the master regulator of lysosomal biogenesis and the autophagy–lysosome system, TFEB has emerged as one of the most compelling organelle-level targets with translational potential (44). In a CRISPR-activation model (Tfeb^CRa), elevation of endogenous TFEB in osteoblasts increased lysosomal abundance, augmented autophagic flux, and enhanced matrix remodeling capacity, ultimately leading to substantial gains in bone mass and mechanical strength (19). These findings establish a strong mechanistic rationale for employing pharmacological agents, small molecules, or gene modulators to activate TFEB as a direct route to reconstitute osteoblastic lysosomal competence and promote bone anabolism.

Within osteoclasts, the RANKL–PKCβ–TFEB signaling axis similarly governs lysosomal biogenesis and offers an attractive window for intervention (94). Modulating this cascade to curb pathological lysosomal expansion may effectively restrain excessive bone resorption while preserving osteoclast metabolic stability (94). Lysosomal dysfunction often accelerates skeletal aging, as SASP derived from senescent osteoblasts and stromal cells degrades ECM integrity and suppresses lysosomal renewal (100). Targeting these senescent populations—either through senolytics to eliminate them or senomorphics to mitigate SASP—has the potential to re-establish ECM quality, relieve inflammatory repression of lysosomal biogenesis, and restore the positive regulatory loop between ECM and lysosomes (172). Beyond intrinsic skeletal cells, tuning the secretory phenotypes of immune cells such as macrophages and T cells toward reparative states may further enhance lysosomal fitness, thereby broadening therapeutic leverage across the ECM–lysosome axis (173, 174).

Regulation of lysosomal trafficking and maturation in osteoclasts also represents a therapeutically powerful strategy. RUFY4, a Rab7–LAMP2 adaptor coordinating late endosome–lysosome fusion, is indispensable for lysosomal maturation (20). Loss of Rufy4 disrupts CatK delivery to the bone interface and diminishes bone resorption without compromising osteoclast viability or differentiation (20). Evidence from OVX and inflammatory high–bone turnover models demonstrates that Rufy4 deficiency preserves trabecular architecture in vivo (175). This mechanism of “selectively blocking lysosomal secretion” offers a refined approach to suppress bone resorption while avoiding pathological lysosomal accumulation. CatK, the predominant lysosome-derived collagenase responsible for type I collagen degradation, remains a major focus of therapeutic development (176). Although classical CatK inhibitors reduce resorption, adverse effects and off-target activities have limited their clinical success (176). Consequently, a new paradigm emphasizing “function-selective inhibition” has emerged, aiming to suppress CatK’s collagenolytic activity while retaining its intracellular proteolytic functions (177). Approaches such as heparan sulfate–mediated CatK dimerization, allosteric inhibitors, and tanshinone-derived natural compounds have demonstrated efficacy in reducing bone resorption while minimizing lysosomal stress (177, 178). Additionally, the non-pyroptotic action of GSDMD—through its p20 fragment binding PI (3)P and thereby hindering endosomal maturation and CatK secretion—illustrates that modulating lysosomal maturation cascades can serve as an indirect yet potent means to regulate CatK activity (179).

Taken together, strategies that boost lysosomal biogenesis in osteoblasts, constrain lysosomal secretion in osteoclasts, eliminate lysosome-defective senescent cells, and achieve function-selective modulation of CatK all converge toward a common goal: rebalancing the ECM–lysosome axis and restoring skeletal homeostasis at the organelle level. These organelle-centric interventions not only reinforce the regenerative capacity of the ECM but also establish a mechanistic framework for designing next-generation osteoporosis therapies that are both more precise and safer (Table 3).

Table 3

Table 3. Intervention strategy targeting the ECM–lysosomal axis.

5.2 Reconstructing the extracellular matrix: matrix-directed repair strategies

Damage to the ECM is frequently an initiating event in osteoporosis (180), and disruptions in ECM composition and structural organization further weaken the lysosome-dependent matrix sensing, cargo recycling, and remodeling capacities of osteoblasts, osteoclasts, and osteocytes (131). Within this conceptual framework, ECM deterioration not only provides the material basis for loss of mechanical strength but also marks the initial point of imbalance within the “ECM–lysosome axis.” Consequently, restoring ECM architecture and function represents a crucial therapeutic opportunity for reversing bone loss and reactivating intracellular–extracellular homeostatic circuits.

Among available strategies, targeting collagen crosslinking is recognized as a central approach to reinforcing the mechanical continuity of the bone matrix (181). The LOX/LOXL2 family, which catalyzes the formation of mature pyridinoline crosslinks, not only governs ECM stability but also modulates the lysosomal metabolic state of osteoblasts. Exogenous supplementation of LOX/LOXL2 has been shown to markedly enhance ECM maturation and structural organization in engineered bone constructs, whereas LOX inhibition disrupts osteogenic differentiation and reduces mineralization efficiency (181). These findings underscore the essential role of promoting physiological crosslink formation to preserve ECM integrity. Importantly, ECM repair is tightly coupled to lysosomal regulation at the molecular level. For instance, activation of OLR1/LOX-1 retains TFEB in the cytosol, thereby suppressing autophagy–lysosome biogenesis (182), highlighting a bidirectional causal relationship between impaired ECM sensing and lysosomal dysfunction.

Beyond biochemical remodeling, strategies aimed at reinforcing the physical attributes of the ECM have also gained traction. Mechanical stimulation via low-intensity pulsed ultrasound (LIPUS) or whole-body vibration (WBV) increases local matrix stiffness, enhances lysosome formation, and augments autophagic flux (182, 183). Such interventions improve mechanosensitivity across bone cells in experimental settings and have shown promising clinical benefits. Notably, high-frequency, low-intensity WBV administered at adequate cumulative doses significantly increases bone mineral density in postmenopausal women (184), providing early evidence for mechanical enhancement as a viable therapeutic avenue.

Collectively, approaches ranging from promoting collagen crosslinking to strengthening ECM mechanical properties converge on the same therapeutic objective: rebuilding the “ECM–lysosome positive feedback loop” that underlies skeletal homeostasis. By restoring ECM structural integrity and reinforcing lysosome-dependent metabolic and mechanosensitive pathways, these matrix-oriented strategies offer a mechanistically grounded and translationally promising direction for combating osteoporosis (Table 3).

5.3 Nanomaterial-based therapies and drug delivery systems

Nanomaterials provide a highly tunable platform for precise manipulation of the ECM–lysosome axis, enabling simultaneous remodeling of the bone microenvironment and intracellular pathways through organelle-targeted delivery. Recent advances demonstrate that nanocarriers based on hydroxyapatite (HAp), metal ions, or biomimetic ECM structures are actively internalized by BMSCs and other bone-related cells, accumulating within endosome–lysosome compartments where they initiate osteogenic signaling cascades (185). For example, cit-Zn-HAp nanoparticles gradually release Zn²⁺ and Ca²⁺ in the acidic lysosomal milieu, stimulating WNT/β-catenin and Runx2 signaling, increasing ALP activity, and enhancing mineralization. These findings indicate that “lysosome-localized ionic modulation” effectively restores disrupted ECM–lysosome coupling (163).Similarly, acid-responsive or pH-sensitive nanocarriers exploit the low pH of lysosomes to achieve precise release of drugs, transcriptional regulators, or autophagy–lysosome modulators, thereby improving lysosomal acidification, augmenting autophagic flux, or restoring ECM turnover (186). Acid-responsive ZIF nanoparticles, for instance, successfully deliver curcumin to bone tissue, and intravenous administration of CZA reduces bone loss in OVX mice (186). By targeting intracellular organelles, these systems not only improve therapeutic efficacy but also minimize nonspecific toxicity associated with systemic drug exposure—making them one of the most promising strategies for modulating the ECM–lysosome axis. Expanding beyond small molecules, both viral and non-viral nanocarriers have been employed for bone-targeted gene delivery to correct congenital lysosome–mineralization defects or potentiate osteogenic pathways. Nevertheless, limited vascularity and the dense ECM structure of bone continue to restrict intratissue drug penetration. Future efforts should focus on optimizing particle size, surface charge, ECM-binding affinity, and lysosomal activation mechanisms to maximize delivery efficiency and achieve sustained regeneration within the bone-defect microenvironment (Table 3).

6 Limitations and prospects

This review centers on the core pathological basis of osteoporosis, beginning with the pressing reality of its global epidemiology and advancing a conceptual framework that positions “ECM–lysosome crosstalk” as a fundamental determinant of skeletal homeostasis. The structural integrity and dynamic renewal of the bone ECM are essential for maintaining mechanical competence and cellular functionality, while lysosomes—through acidification, proteolysis, autophagy flux regulation, and inter-organelle metabolic coupling—govern ECM turnover and microenvironmental equilibrium. Here, we systematically delineate the lysosome-dependent roles of osteoclasts, osteoblasts, and osteocytes in ECM regulation, emphasizing how the biochemical composition, mechanical properties, and nanoscale topology of the ECM profoundly shape lysosomal biogenesis, functional states, and signaling outputs. Disruption of this bidirectional ECM–lysosome axis is pervasive across the onset and progression of osteoporosis, manifested by heightened osteoclast acidification and secretion, impaired autophagy–mitochondrial coupling in osteoblasts, and collapse of osteocytic PLR and the lacunar–canalicular system—all highlighting the centrality of this signaling network.

Despite growing interest in ECM–lysosome crosstalk, major mechanistic gaps remain. The temporal and spatial specificity with which lysosomal dynamics participate in lineage differentiation and matrix remodeling is still insufficiently defined. Most current evidence derives from cell-based or animal studies, and translation into clinically actionable biomarkers or drug targets remains limited. Moreover, the principles underlying intercellular lysosomal communication—such as cross-talk between osteoblasts and osteoclasts or between BMSCs and immune cells—are only beginning to be uncovered. Future research would benefit from integrating spatial transcriptomics, single-cell multi-omics, and high-resolution imaging to construct a more comprehensive spatiotemporal regulatory map. On the therapeutic front, agents targeting lysosomal function, including small molecules and nanodelivery platforms such as pH-responsive carriers and lysosome-stabilizing compounds, are emerging as promising interventions. Recent studies demonstrate that modulating TFEB nuclear translocation, inhibiting mTOR, or deploying acid-stabilizing agents can markedly attenuate osteoclast hyperactivation and rescue impaired osteogenesis, underscoring strong translational potential.

Taken together, ECM–lysosome crosstalk represents a pivotal bridge linking cellular metabolism with matrix remodeling, and its conceptual and mechanistic maturation holds substantial promise for advancing osteoporosis research and treatment. Continued interdisciplinary collaboration—integrating materials science, systems biology, and nanotechnology—will be essential for elucidating the molecular foundations, tissue-specific properties, and clinical relevance of this crosstalk. Such efforts are expected to provide a robust foundation for precision prevention and individualized therapy in osteoporosis.

Author contributions

CZ: Writing – original draft. XH: Writing – original draft. YJ: Writing – original draft. JZ: Writing – review & editing. JT: Writing – review & editing. XO: Writing – review & editing. JQT: Writing – review & editing. GZ: Writing – review & editing. HL: Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. Guiding Science and Technology Plan Project of Changsha City in 2022 (grant no. kzd22005), Hunan Provincial Natural Science Foundation Project in 2025 (grant nos. 2025JJ90029, 2025JJ90014).

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Hoong CWS, Saul D, Khosla S, and Sfeir JG. Advances in the management of osteoporosis. BMJ. (2025) 390:e081250. doi: 10.1136/bmj-2024-081250

PubMed Abstract | Crossref Full Text | Google Scholar

2. Xu J, Yu L, Liu F, Wan L, and Deng Z. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol. (2023) 14:1222129. doi: 10.3389/fimmu.2023.1222129

PubMed Abstract | Crossref Full Text | Google Scholar

3. Liang H, Chen S, Shi M, Xu J, Zhao C, Yang B, et al. Global epidemiology and burden of osteoporosis among postmenopausal women: insights from the Global Burden of Disease Study 2021. NPJ Aging. (2025) 11:78. doi: 10.1038/s41514-025-00269-2

PubMed Abstract | Crossref Full Text | Google Scholar

4. Tay WL and Tay D. Discontinuing denosumab: can it be done safely? A review of the literature. Endocrinol Metab (Seoul). (2022) 37:183–94. doi: 10.3803/EnM.2021.1369

PubMed Abstract | Crossref Full Text | Google Scholar

5. Ahdi HS, Wichelmann TA, Pandravada S, and Ehrenpreis ED. Medication-induced osteonecrosis of the jaw: a review of cases from the Food and Drug Administration Adverse Event Reporting System (FAERS). BMC Pharmacol Toxicol. (2023) 24:15. doi: 10.1186/s40360-023-00657-y

PubMed Abstract | Crossref Full Text | Google Scholar

6. Chen Y, Klein-Nulend J, and Bravenboer N. Ageing-related changes in ultrastructural bone matrix composition and osteocyte mechanosensitivity. Curr Osteoporos Rep. (2025) 23:35. doi: 10.1007/s11914-025-00927-0

PubMed Abstract | Crossref Full Text | Google Scholar

7. Bertels JC, He G, and Long F. Metabolic reprogramming in skeletal cell differentiation. Bone Res. (2024) 12:57. doi: 10.1038/s41413-024-00374-0

PubMed Abstract | Crossref Full Text | Google Scholar

8. Zhu S, Chen W, Masson A, and Li YP. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discov. (2024) 10:71. doi: 10.1038/s41421-024-00689-6

PubMed Abstract | Crossref Full Text | Google Scholar

9. Delgado-Calle J and Bellido T. The osteocyte as a signaling cell. Physiol Rev. (2022) 102:379–410. doi: 10.1152/physrev.00043.2020

PubMed Abstract | Crossref Full Text | Google Scholar

10. Di X, Gao X, Peng L, Ai J, Jin X, Qi S, et al. Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets. Signal Transduct Target Ther. (2023) 8:282. doi: 10.1038/s41392-023-01501-9

PubMed Abstract | Crossref Full Text | Google Scholar

11. Qin S, Davern K, Wilson SG, Chen K, Li A, and Xu J. Lysosome-iron-mitochondria axis in osteoclasts: iron as a central player. Res (Wash D C). (2025) 8:840. doi: 10.34133/research.0840

PubMed Abstract | Crossref Full Text | Google Scholar

12. Settembre C and Perera RM. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat Rev Mol Cell Biol. (2024) 25:223–45. doi: 10.1038/s41580-023-00676-x

PubMed Abstract | Crossref Full Text | Google Scholar

13. Nowosad A and Besson A. Lysosomes at the crossroads of cell metabolism, cell cycle, and stemness. Int J Mol Sci. (2022) 23:2290. doi: 10.3390/ijms23042290

PubMed Abstract | Crossref Full Text | Google Scholar

14. Chavan I and Bhattacharjee A. Lysosome heterogeneity and diversity mapped through its distinct cellular functions. Cell Mol Life Sci. (2025) 82:380. doi: 10.1007/s00018-025-05883-7

PubMed Abstract | Crossref Full Text | Google Scholar

15. Lee SH, JS J, Mo S, and Kim HH. TMEM175 plays a crucial role in osteoblast differentiation by regulating lysosomal function and autophagy. Mol Cells. (2024) 47:100127. doi: 10.1016/j.mocell.2024.100127

PubMed Abstract | Crossref Full Text | Google Scholar

16. Jiang J, Ren R, Fang W, Miao J, Wen Z, Wang X, et al. Lysosomal biogenesis and function in osteoclasts: a comprehensive review. Front Cell Dev Biol. (2024) 12:1431566. doi: 10.3389/fcell.2024.1431566

PubMed Abstract | Crossref Full Text | Google Scholar

17. Wang J, Zhang Y, Cao J, Wang Y, Anwar N, Zhang Z, et al. The role of autophagy in bone metabolism and clinical significance. Autophagy. (2023) 19:2409–27. doi: 10.1080/15548627.2023.2186112

PubMed Abstract | Crossref Full Text | Google Scholar

18. Yang Q, Ma H, Yang L, Jiang M, Liu X, and Bai Z. Decoding extracellular matrix-lysosome cross-talk and its implications for neurodegenerative diseases. Sci Signal. (2025) 18:eadt1936. doi: 10.1126/scisignal.adt1936

PubMed Abstract | Crossref Full Text | Google Scholar

19. James A, Hendrixson JA, Kadhim I, Marques-Carvalho A, Laster J, Crawford J, et al. Elevation of master autophagy regulator Tfeb in osteoblast lineage cells increases bone mass and strength. JCI Insight. (2025) 10:e191688. doi: 10.1172/jci.insight.191688

PubMed Abstract | Crossref Full Text | Google Scholar

20. Kim M, Park JH, Go M, Lee N, Seo J, Lee H, et al. RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts. Bone Res. (2024) 12:29. doi: 10.1038/s41413-024-00326-8

PubMed Abstract | Crossref Full Text | Google Scholar

21. Lachuer H, Le L, Lévêque-Fort S, Goud B, and Schauer K. Spatial organization of lysosomal exocytosis relies on membrane tension gradients. Proc Natl Acad Sci U S A. (2023) 120:e2207425120. doi: 10.1073/pnas.2207425120

PubMed Abstract | Crossref Full Text | Google Scholar

22. Ribet ABP, Ng PY, and Pavlos NJ. Membrane transport proteins in osteoclasts: the ins and outs. Front Cell Dev Biol. (2021) 9:644986. doi: 10.3389/fcell.2021.644986

PubMed Abstract | Crossref Full Text | Google Scholar

23. Duan X, Yang S, Zhang L, and Yang T. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics. (2018) 8:5379–99. doi: 10.7150/thno.28391

PubMed Abstract | Crossref Full Text | Google Scholar

24. Salcedo-Betancourt JD and Moe OW. The effects of acid on calcium and phosphate metabolism. Int J Mol Sci. (2024) 25:2081. doi: 10.3390/ijms25042081

PubMed Abstract | Crossref Full Text | Google Scholar

25. Delaisse JM, Søe K, TL A, AM R, and Marcussen N. The mechanism switching the osteoclast from short to long duration bone resorption. Front Cell Dev Biol. (2021) 9:644503. doi: 10.3389/fcell.2021.644503

PubMed Abstract | Crossref Full Text | Google Scholar

26. Chen Y, Yang S, Lovisa S, Ambrose CG, McAndrews KM, Sugimoto H, et al. Type-I collagen produced by distinct fibroblast lineages reveals specific function during embryogenesis and Osteogenesis Imperfecta. Nat Commun. (2021) 12:7199. doi: 10.1038/s41467-021-27563-3

PubMed Abstract | Crossref Full Text | Google Scholar

27. Mijanović O, Jakovleva A, Branković A, Zdravkova K, Pualic M, Belozerskaya TA, et al. Cathepsin K in pathological conditions and new therapeutic and diagnostic perspectives. Int J Mol Sci. (2022) 23:13762. doi: 10.3390/ijms232213762

PubMed Abstract | Crossref Full Text | Google Scholar

28. Capo V, Abinun M, and Villa A. Osteoclast rich osteopetrosis due to defects in the TCIRG1 gene. Bone. (2022) 165:116519. doi: 10.1016/j.bone.2022.116519

PubMed Abstract | Crossref Full Text | Google Scholar

29. Zifarelli G. The role of the lysosomal cl-/H+ Antiporter clC-7 in osteopetrosis and neurodegeneration. Cells. (2022) 11:366. doi: 10.3390/cells11030366

PubMed Abstract | Crossref Full Text | Google Scholar

30. Penna S, Villa A, and Capo V. Autosomal recessive osteopetrosis: mechanisms and treatments. Dis Model Mech. (2021) 14:dmm048940. doi: 10.1242/dmm.048940

PubMed Abstract | Crossref Full Text | Google Scholar

31. Chen Y, Zhou L, Guan X, Wen X, Yu J, and Dou Y. Case report: Gene mutations and clinical characteristics of four patients with osteopetrosis. Front Pediatr. (2023) 11:1096770. doi: 10.3389/fped.2023.1096770

PubMed Abstract | Crossref Full Text | Google Scholar

32. Sobacchi C, Villa A, Schulz A, and Kornak U. CLCN7-related osteopetrosis. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, and Amemiya A, editors. GeneReviews^®. Seattle (WA): University of Washington, Seattle (2007).

PubMed Abstract | Google Scholar

33. Shen S, Si M, Zeng C, Liu EK, Chen Y, Vacher J, et al. Leucine repeat rich kinase 1 controls osteoclast activity by managing lysosomal trafficking and secretion. Biol (Basel). (2023) 12:511. doi: 10.3390/biology12040511

PubMed Abstract | Crossref Full Text | Google Scholar

34. Devignes CS, Carmeliet G, and Stegen S. Amino acid metabolism in skeletal cells. Bone Rep. (2022) 17:101620. doi: 10.1016/j.bonr.2022.101620

PubMed Abstract | Crossref Full Text | Google Scholar

35. Fernandes SA, Angelidaki DD, Nüchel J, Pan J, Gollwitzer P, Elkis Y, et al. Spatial and functional separation of mTORC1 signalling in response to different amino acid sources. Nat Cell Biol. (2024) 26:1918–33. doi: 10.1038/s41556-024-01523-7

PubMed Abstract | Crossref Full Text | Google Scholar

36. Cui Z, Napolitano G, de Araujo MEG, Esposito A, Monfregola J, Huber LA, et al. Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. Nature. (2023) 614:572–9. doi: 10.1038/s41586-022-05652-7

PubMed Abstract | Crossref Full Text | Google Scholar

37. Egri SB, Ouch C, Chou HT, Yu Z, Song K, Xu C, et al. Cryo-EM structures of the human GATOR1-Rag-Ragulator complex reveal a spatial-constraint regulated GAP mechanism. Mol Cell. (2022) 82:1836–1849.e5. doi: 10.1016/j.molcel.2022.03.002

PubMed Abstract | Crossref Full Text | Google Scholar

38. Lama-Sherpa TD, Jeong MH, and Jewell JL. Regulation of mTORC1 by the rag GTPases. Biochem Soc Trans. (2023) 51:655–64. doi: 10.1042/BST20210038

PubMed Abstract | Crossref Full Text | Google Scholar

39. Meng D, Yang Q, Melick CH, Park BC, Hsieh TS, Curukovic A, et al. ArfGAP1 inhibits mTORC1 lysosomal localization and activation. EMBO J. (2021) 29:426–432.e8. doi: 10.15252/embj.2020106412

PubMed Abstract | Crossref Full Text | Google Scholar

40. Lei HT, Mu X, Hattne J, and Gonen T. A conformational change in the N terminus of SLC38A9 signals mTORC1 activation. Structure. (2021) 29:426–432.e8. doi: 10.1016/j.str.2020.11.014

PubMed Abstract | Crossref Full Text | Google Scholar

41. Han L, Li F, Wu H, Wang W, Chen P, Xia W, et al. Targeting FABP4 to inhibit AGEs-RAGE/NF-κB signalling effectively ameliorates nucleus pulposus dysfunction and angiogenesis in obesity-related intervertebral disc degeneration. Cell Prolif. (2025) 58:e70021. doi: 10.1111/cpr.70021

PubMed Abstract | Crossref Full Text | Google Scholar

42. Igarashi N, Honjo M, and Aihara M. mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells. Sci Rep. (2021) 11:14111. doi: 10.1038/s41598-021-93580-3

PubMed Abstract | Crossref Full Text | Google Scholar

43. Xing Y, Liu C, Zhou L, Li Y, and Wu D. Osteogenic effects of rapamycin on bone marrow mesenchymal stem cells via inducing autophagy. J Orthop Surg Res. (2023) 18:129. doi: 10.1186/s13018-023-03616-9

PubMed Abstract | Crossref Full Text | Google Scholar

44. Mahapatra KK, Mishra SR, Behera BP, Patil S, Gewirtz DA, and Bhutia SK. The lysosome as an imperative regulator of autophagy and cell death. Cell Mol Life Sci. (2021) 78:7435–49. doi: 10.1007/s00018-021-03988-3

PubMed Abstract | Crossref Full Text | Google Scholar

45. He M, Lei H, He X, Liu Y, Wang A, Ren Z, et al. METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis. Stem Cells Transl Med. (2022) 11:987–1001. doi: 10.1093/stcltm/szac049

PubMed Abstract | Crossref Full Text | Google Scholar

46. Ito M, Yurube T, Kanda Y, Kakiuchi Y, Takeoka Y, Takada T, et al. Inhibition of Autophagy at Different Stages by ATG5 Knockdown and Chloroquine Supplementation Enhances Consistent Human Disc Cellular Apoptosis and Senescence Induction rather than Extracellular Matrix Catabolism. Int J Mol Sci. (2021) 22:3965. doi: 10.3390/ijms22083965

PubMed Abstract | Crossref Full Text | Google Scholar

47. Le TV, Phan-Thi HT, Huynh-Thi MX, Dang TM, Le Holterman AX, Grassi G, et al. Autophagy inhibitor chloroquine downmodulates hepatic stellate cell activation and liver damage in bile-duct-ligated mice. Cells. (2023) 12:1025. doi: 10.3390/cells12071025

PubMed Abstract | Crossref Full Text | Google Scholar

48. Kacal M, Zhang B, Hao Y, Norberg E, and Vakifahmetoglu-Norberg H. Quantitative proteomic analysis of temporal lysosomal proteome and the impact of the KFERQ-like motif and LAMP2A in lysosomal targeting. Autophagy. (2021) 17:3865–74. doi: 10.1080/15548627.2021.1876343

PubMed Abstract | Crossref Full Text | Google Scholar

49. Reynolds CA, Pelka S, Gjergjova F, Tasset I, Khawaja RR, Lindenau K, et al. Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function. Proc Natl Acad Sci U S A. (2024) 121:e2322929121. doi: 10.1073/pnas.2322929121

PubMed Abstract | Crossref Full Text | Google Scholar

50. Endicott SJ. Chaperone-mediated autophagy as a modulator of aging and longevity. Front Aging. (2024) 5:1509400. doi: 10.3389/fragi.2024.1509400

PubMed Abstract | Crossref Full Text | Google Scholar

51. Akel N, MacLeod RS, Berryhill SB, Laster DJ, Dimori M, Crawford JA, et al. Loss of chaperone-mediated autophagy is associated with low vertebral cancellous bone mass. Sci Rep. (2022) 12:3134. doi: 10.1038/s41598-022-07157-9

PubMed Abstract | Crossref Full Text | Google Scholar

52. Bourdenx M, Martı́n-Segura A, Scrivo A, Rodriguez-Navarro JA, Kaushik S, Tasset I, et al. Chaperone-mediated autophagy prevents collapse of the neuronal metasta ble proteome. Cell. (2021) 184:2696–2714.e25. doi: 10.1016/j.cell.2021.03.048

PubMed Abstract | Crossref Full Text | Google Scholar

53. Luo Z, Wei W, Qiu D, Su Z, Liu L, Zhou H, et al. Rejuvenation of BMSCs senescence by pharmacological enhancement of TFEB-mediated autophagy alleviates aged-related bone loss and extends lifespan in middle aged mice. Bone Res. (2024) 12:45. doi: 10.1038/s41413-024-00351-7

PubMed Abstract | Crossref Full Text | Google Scholar

54. Tang Y, Bie M, Zhang Q, Cong R, Pan C, Xia Y, et al. Ctsk+ Osteoclasts orchestrate condylar morphogenesis via hypoxic lysosome. J Dent Res. (2025). doi: 10.1177/00220345251369411

PubMed Abstract | Crossref Full Text | Google Scholar

55. Lin Y, Shi Q, Yang G, Shi F, Zhou Y, Wang T, et al. A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB. Proc Natl Acad Sci U S A. (2023) 120:e2213670120. doi: 10.1073/pnas.2213670120

PubMed Abstract | Crossref Full Text | Google Scholar

56. Fang Q, Jing G, Zhang Y, Wang H, Luo H, Xia Y, et al. Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries. J Transl Med. (2023) 21:916. doi: 10.1186/s12967-023-04796-y

PubMed Abstract | Crossref Full Text | Google Scholar

57. Yoneshima E, Okamoto K, Sakai E, Nishishita K, Yoshida N, and Tsukuba T. The transcription factor EB (TFEB) regulates osteoblast differentiation through ATF4/CHOP-dependent pathway. J Cell Physiol. (2016) 231:1321–33. doi: 10.1002/jcp.25235

PubMed Abstract | Crossref Full Text | Google Scholar

58. Dai R, Wu Z, Chu HY, Lu J, Lyu A, Liu J, et al. Cathepsin K: the action in and beyond bone. Front Cell Dev Biol. (2020) 8:433. doi: 10.3389/fcell.2020.00433

PubMed Abstract | Crossref Full Text | Google Scholar

59. Gao L, Liu G, Wu X, Liu C, Wang Y, Ma M, et al. Osteocytes autophagy mediated by mTORC2 activation controls osteoblasts differentiation and osteoclasts activities under mechanical loading. Arch Biochem Biophys. (2023) 742:109634. doi: 10.1016/j.abb.2023.109634

PubMed Abstract | Crossref Full Text | Google Scholar

60. Ng PY, Brigitte PRA, and Pavlos NJ. Membrane trafficking in osteoclasts and implications for osteoporosis. Biochem Soc Trans. (2019) 47:639–50. doi: 10.1042/BST20180445

PubMed Abstract | Crossref Full Text | Google Scholar

61. Qin A, Cheng TS, Lin Z, Pavlos NJ, Jiang Q, Xu J, et al. Versatile roles of V-ATPases accessory subunit Ac45 in osteoclast formation and function. PloS One. (2011) 6:e27155. doi: 10.1371/journal.pone.0027155

PubMed Abstract | Crossref Full Text | Google Scholar

62. Takegahara N, Kim H, and Choi Y. Unraveling the intricacies of osteoclast differentiation and maturation: insight into novel therapeutic strategies for bone-destructive diseases. Exp Mol Med. (2024) 56:264–72. doi: 10.1038/s12276-024-01157-7

PubMed Abstract | Crossref Full Text | Google Scholar

63. Iwayama T, Okada T, Ueda T, Tomita K, Matsumoto S, Takedachi M, et al. Osteoblastic lysosome plays a central role in mineralization. Sci Adv. (2019) 5:eaax0672. doi: 10.1126/sciadv.aax0672

PubMed Abstract | Crossref Full Text | Google Scholar

64. Margiotta A. Coupling of intracellular calcium homeostasis and formation and secretion of matrix vesicles: their role in the mechanism of biomineralization. Cells. (2025) 14:733. doi: 10.3390/cells14100733

PubMed Abstract | Crossref Full Text | Google Scholar

65. Li W, Jiang WS, Su YR, Tu KW, Zou L, Liao CR, et al. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis. (2023) 14:88. doi: 10.1038/s41419-023-05595-5

PubMed Abstract | Crossref Full Text | Google Scholar

66. Qin L, Liu W, Cao H, and Xiao G. Molecular mechanosensors in osteocytes. Bone Res. (2020) 8:23. doi: 10.1038/s41413-020-0099-y

PubMed Abstract | Crossref Full Text | Google Scholar

67. van Tol AF, Schemenz V, Wagermaier W, Roschger A, Razi H, Vitienes I, et al. The mechanoresponse of bone is closely related to the osteocyte lacunocanalicular network architecture. Proc Natl Acad Sci U S A. (2020) 117:32251–9. doi: 10.1073/pnas.2011504117

PubMed Abstract | Crossref Full Text | Google Scholar

68. Xu H, Xia M, Sun L, Wang H, and Zhang WB. Osteocytes enhance osteogenesis by autophagy-mediated FGF23 secretion under mechanical tension. Front Cell Dev Biol. (2022) 9:782736. doi: 10.3389/fcell.2021.782736

PubMed Abstract | Crossref Full Text | Google Scholar

69. Hua R, Truong VA, Fajardo RJ, Guda T, Gu S, and Jiang JX. Connexin hemichannels drive lactation-induced osteocyte acidification and perilacunar-canalicular remodeling. Cell Rep. (2024) 43:114363. doi: 10.1016/j.celrep.2024.114363

PubMed Abstract | Crossref Full Text | Google Scholar

70. Lotinun S, Ishihara Y, Nagano K, Kiviranta R, Carpentier VT, Neff L, et al. Cathepsin K-deficient osteocytes prevent lactation-induced bone loss and parathyroid hormone suppression. J Clin Invest. (2019) 129:3058–71. doi: 10.1172/JCI122936

PubMed Abstract | Crossref Full Text | Google Scholar

71. Li W, Zhao J, Sun W, Wang H, Pan Y, Wang L, et al. Osteocytes promote osteoclastogenesis via autophagy-mediated RANKL secretion under mechanical compressive force. Arch Biochem Biophys. (2020) 694:108594. doi: 10.1016/j.abb.2020.108594

PubMed Abstract | Crossref Full Text | Google Scholar

72. Wang ZX, Lin X, Cao J, Liu YW, Luo ZW, Rao SS, et al. Young osteocyte-derived extracellular vesicles facilitate osteogenesis by transferring tropomyosin-1. J Nanobiotechnology. (2024) 22:208. doi: 10.1186/s12951-024-02367-x

PubMed Abstract | Crossref Full Text | Google Scholar

73. Ruiz-Blázquez P, Fernández-Fernández M, Pistorio V, Martinez-Sanchez C, Costanzo M, Iruzubieta P, et al. Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis. Mol Metab. (2024) 87:101989. doi: 10.1016/j.molmet.2024.101989

PubMed Abstract | Crossref Full Text | Google Scholar

74. Wu M, Wu S, Chen W, and Li YP. The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res. (2024) 34:101–23. doi: 10.1038/s41422-023-00918-9

PubMed Abstract | Crossref Full Text | Google Scholar

75. Choi IA, Umemoto A, Mizuno M, and Park-Min KH. Bone metabolism - an underappreciated player. NPJ Metab Health Dis. (2024) 2:12. doi: 10.1038/s44324-024-00010-9

PubMed Abstract | Crossref Full Text | Google Scholar

76. Murshid SA. Bone permeability and mechanotransduction: Some current insights into the function of the lacunar-canalicular network. Tissue Cell. (2022) 75:101730. doi: 10.1016/j.tice.2022.101730

PubMed Abstract | Crossref Full Text | Google Scholar

77. Dirckx N, Zhang Q, Chu EY, Tower RJ, Li Z, Guo S, et al. A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth. Proc Natl Acad Sci U S A. (2022) 119:e2212178119. doi: 10.1073/pnas.2212178119

PubMed Abstract | Crossref Full Text | Google Scholar

78. Liu W, Cheong N, He Z, and Zhang T. Application of hydroxyapatite composites in bone tissue engineering: A review. J Funct Biomater. (2025) 16:127. doi: 10.3390/jfb16040127

PubMed Abstract | Crossref Full Text | Google Scholar

79. Chu A, Zirngibl RA, and Manolson MF. The V-ATPase a3 subunit: structure, function and therapeutic potential of an essential biomolecule in osteoclastic bone resorption. Int J Mol Sci. (2021) 22:6934. doi: 10.3390/ijms22136934

PubMed Abstract | Crossref Full Text | Google Scholar

80. Chen F, Kang R, Liu J, and Tang D. The V-ATPases in cancer and cell death. Cancer Gene Ther. (2022) 29:1529–41. doi: 10.1038/s41417-022-00477-y

PubMed Abstract | Crossref Full Text | Google Scholar

81. Zhong D, Wang R, Zhang H, Wang M, Zhang X, and Chen H. Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity. Nat Commun. (2023) 14:3997. doi: 10.1038/s41467-023-39716-7

PubMed Abstract | Crossref Full Text | Google Scholar

82. Di Malta C, Zampelli A, Granieri L, Vilardo C, De Cegli R, Cinque L, et al. TFEB and TFE3 drive kidney cystogenesis and tumorigenesis. EMBO Mol Med. (2023) 15:e16877. doi: 10.15252/emmm.202216877

PubMed Abstract | Crossref Full Text | Google Scholar

83. Kunishige R, Mizoguchi M, Tsubouchi A, Hanaoka K, Miura Y, Kurosu H, et al. Calciprotein particle-induced cytotoxicity via lysosomal dysfunction and altered cholesterol distribution in renal epithelial HK-2 cells. Sci Rep. (2020) 10:20125. doi: 10.1038/s41598-020-77308-3

PubMed Abstract | Crossref Full Text | Google Scholar

84. Feenstra L, Kutikhin AG, Shishkova DK, Buikema H, Zeper LW, Bourgonje AR, et al. Calciprotein particles induce endothelial dysfunction by impairing endothelial nitric oxide metabolism. Arterioscler Thromb Vasc Biol. (2023) 43:443–55. doi: 10.1161/ATVBAHA.122.318420

PubMed Abstract | Crossref Full Text | Google Scholar

85. Smith ER and Holt SG. The formation and function of calciprotein particles. Pflugers Arch. (2025) 477:753–72. doi: 10.1007/s00424-025-03083-7

PubMed Abstract | Crossref Full Text | Google Scholar

86. Pang X, He X, Qiu Z, Zhang H, Xie R, Liu Z, et al. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct Target Ther. (2023) 8:1. doi: 10.1038/s41392-022-01259-6

PubMed Abstract | Crossref Full Text | Google Scholar

87. Cuellar-Vite L, Weber-Bonk KL, Abdul-Karim FW, Booth CN, and Keri RA. Focal adhesion kinase provides a collateral vulnerability that can be leveraged to improve mTORC1 inhibitor efficacy. Cancers (Basel). (2022) 14:3374. doi: 10.3390/cancers14143374

PubMed Abstract | Crossref Full Text | Google Scholar

88. Daponte V, Henke K, and Drissi H. Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast-osteoblast communication and potential clinical implications. Elife. (2024) 13:e95083. doi: 10.7554/eLife.95083

PubMed Abstract | Crossref Full Text | Google Scholar

89. Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R, et al. Lysosomal calcium signalling regulates autophagy through calcineurin and ​TFEB. Nat Cell Biol. (2015) 17:288–99. doi: 10.1038/ncb3114

PubMed Abstract | Crossref Full Text | Google Scholar

90. Park K, Lim H, Kim J, Hwang Y, Lee YS, Bae SH, et al. Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress. Nat Commun. (2022) 13:1300. doi: 10.1038/s41467-022-28874-9

PubMed Abstract | Crossref Full Text | Google Scholar

91. Liu Q, Busby JC, and Molkentin JD. Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nat Cell Biol. (2009) 11:154–61. doi: 10.1038/ncb1823

PubMed Abstract | Crossref Full Text | Google Scholar

92. De Leon-Oliva D, Barrena-Blázquez S, Jiménez-Álvarez L, Fraile-Martinez O, García-Montero C, López-González L, et al. The RANK-RANKL-OPG system: A multifaceted regulator of homeostasis, immunity, and cancer. Med (Kaunas). (2023) 59:1752. doi: 10.3390/medicina59101752

PubMed Abstract | Crossref Full Text | Google Scholar

93. Zheng H, Liu Y, Deng Y, Li Y, Liu S, Yang Y, et al. Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets. Mol Med. (2024) 30:20. doi: 10.1186/s10020-024-00788-w

PubMed Abstract | Crossref Full Text | Google Scholar

94. Ferron M, Settembre C, Shimazu J, Lacombe J, Kato S, Rawlings DJ, et al. A RANKL-PKCβ-TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts. Genes Dev. (2013) 27:955–69. doi: 10.1101/gad.213827.113

PubMed Abstract | Crossref Full Text | Google Scholar

95. Yeh SA, Hou J, Wu JW, Yu S, Zhang Y, Belfield KD, et al. Quantification of bone marrow interstitial pH and calcium concentration by intravital ratiometric imaging. Nat Commun. (2022) 13:393. doi: 10.1038/s41467-022-27973-x

PubMed Abstract | Crossref Full Text | Google Scholar

96. Hou X, Zhang L, Zhou Z, Luo X, Wang T, Zhao X, et al. Calcium phosphate-based biomaterials for bone repair. J Funct Biomater. (2022) 13:187. doi: 10.3390/jfb13040187

PubMed Abstract | Crossref Full Text | Google Scholar

97. Ferrari V, Tedesco B, Cozzi M, Chierichetti M, Casarotto E, Pramaggiore P, et al. Lysosome quality control in health and neurodegenerative diseases. Cell Mol Biol Lett. (2024) 29:116. doi: 10.1186/s11658-024-00633-2

PubMed Abstract | Crossref Full Text | Google Scholar

98. Wang H, Zhu Y, Liu H, Liang T, and Wei Y. Advances in drug discovery targeting lysosomal membrane proteins. Pharm (Basel). (2023) 16:601. doi: 10.3390/ph16040601

PubMed Abstract | Crossref Full Text | Google Scholar

99. Pihán P, Lisbona F, Borgonovo J, Edwards-Jorquera S, Nunes-Hasler P, Castillo K, et al. Control of lysosomal-mediated cell death by the pH-dependent calcium channel RECS1. Sci Adv. (2021) 7:eabe5469. doi: 10.1126/sciadv.abe5469

PubMed Abstract | Crossref Full Text | Google Scholar

100. Tan JX and Finkel T. Lysosomes in senescence and aging. EMBO Rep. (2023) 24:e57265. doi: 10.15252/embr.202357265

PubMed Abstract | Crossref Full Text | Google Scholar

101. Liu S, Perez P, Sun X, Chen K, Fatirkhorani R, Mammadova J, et al. MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis. Cell Death Differ. (2024) 31:40–52. doi: 10.1038/s41418-023-01237-7

PubMed Abstract | Crossref Full Text | Google Scholar

102. Malik N, Ferreira BI, Hollstein PE, Curtis SD, Trefts E, Weiser Novak S, et al. Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. Science. (2023) 380:eabj5559. doi: 10.1126/science.abj5559

PubMed Abstract | Crossref Full Text | Google Scholar

103. Na J, Yang Z, Shi Q, Li C, Liu Y, Song Y, et al. Extracellular matrix stiffness as an energy metabolism regulator drives osteogenic differentiation in mesenchymal stem cells. Bioact Mater. (2024) 35:549–63. doi: 10.1016/j.bioactmat.2024.02.003

PubMed Abstract | Crossref Full Text | Google Scholar

104. Lee SY, Kim SJ, Park KH, Lee G, Oh Y, Ryu JH, et al. Differential but complementary roles of HIF-1α and HIF-2α in the regulation of bone homeostasis. Commun Biol. (2024) 7:892. doi: 10.1038/s42003-024-06581-z

PubMed Abstract | Crossref Full Text | Google Scholar

105. You J, Liu M, Li M, Zhai S, Quni S, Zhang L, et al. The role of HIF-1α in bone regeneration: A new direction and challenge in bone tissue engineering. Int J Mol Sci. (2023) 24:8029. doi: 10.3390/ijms24098029

PubMed Abstract | Crossref Full Text | Google Scholar

106. Chen T, Lin X, Lu S, and Li B. V-ATPase in cancer: mechanistic insights and therapeutic potentials. Cell Commun Signal. (2024) 22:613. doi: 10.1186/s12964-024-01998-9

PubMed Abstract | Crossref Full Text | Google Scholar

107. Zhang J, Zeng W, Han Y, Lee WR, Liou J, and Jiang Y. Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel. Mol Cell. (2023) 83:2524–2539.e7. doi: 10.1016/j.molcel.2023.06.004

PubMed Abstract | Crossref Full Text | Google Scholar

108. Paquette M, El-Houjeiri L, Zirden LC, Puustinen P, Blanchette P, Jeong H, et al. AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3. Autophagy. (2021) 17:3957–75. doi: 10.1080/15548627.2021.1898748

PubMed Abstract | Crossref Full Text | Google Scholar

109. Yan R, Zhang P, Shen S, Zeng Y, Wang T, Chen Z, et al. Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion. Nat Immunol. (2024) 25:483–95. doi: 10.1038/s41590-023-01719-3

PubMed Abstract | Crossref Full Text | Google Scholar

110. Al Rifai O, Chow J, Lacombe J, Julien C, Faubert D, Susan-Resiga D, et al. Proprotein convertase furin regulates osteocalcin and bone endocrine function. J Clin Invest. (2017) 127:4104–17. doi: 10.1172/JCI93437

PubMed Abstract | Crossref Full Text | Google Scholar

111. Cheng B, Wan W, Huang G, Li Y, Genin GM, Mofrad MRK, et al. Nanoscale integrin cluster dynamics controls cellular mechanosensing via FAKY397 phosphorylation. Sci Adv. (2020) 6:eaax1909. doi: 10.1126/sciadv.aax1909

PubMed Abstract | Crossref Full Text | Google Scholar

112. Han SJ, Azarova EV, Whitewood AJ, Bachir A, Guttierrez E, Groisman A, et al. Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation. Elife. (2021) 10:e66151. doi: 10.7554/eLife.66151

PubMed Abstract | Crossref Full Text | Google Scholar

113. Cai X, Wang KC, and Meng Z. Mechanoregulation of YAP and TAZ in cellular homeostasis and disease progression. Front Cell Dev Biol. (2021) 9:673599. doi: 10.3389/fcell.2021.673599

PubMed Abstract | Crossref Full Text | Google Scholar

114. Ikeda S, Nah J, Shirakabe A, Zhai P, Oka SI, Sciarretta S, et al. YAP plays a crucial role in the development of cardiomyopathy in lysosomal storage diseases. J Clin Invest. (2021) 131:e143173. doi: 10.1172/JCI143173

PubMed Abstract | Crossref Full Text | Google Scholar

115. Ong YT, Andrade J, Armbruster M, Shi C, Castro M, Costa ASH, et al. A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth. Nat Metab. (2022) 4:672–82. doi: 10.1038/s42255-022-00584-y

PubMed Abstract | Crossref Full Text | Google Scholar

116. Ratto E, Chowdhury SR, Siefert NS, Schneider M, Wittmann M, Helm D, et al. Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly. Nat Commun. (2022) 13:4848. doi: 10.1038/s41467-022-32515-6

PubMed Abstract | Crossref Full Text | Google Scholar

117. Reddy A, Bozi LHM, Yaghi OK, Mills EL, Xiao H, Nicholson HE, et al. pH-gated succinate secretion regulates muscle remodeling in response to exercise. Cell. (2020) 183:62–75.e17. doi: 10.1016/j.cell.2020.08.039

PubMed Abstract | Crossref Full Text | Google Scholar

118. Huang S, Shangguan R, Chen S, Lai X, Han H, and Sun J. Mechanism of fatty acid metabolism and regulation by lactate during exercise in white adipose and skeletal muscle tissue: A review. Sports Med Open. (2025) 11:76. doi: 10.1186/s40798-025-00862-5

PubMed Abstract | Crossref Full Text | Google Scholar

119. Lu S, Li J, Li Y, Liu S, Liu Y, Liang Y, et al. Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism. Sci Transl Med. (2025) 17:eadr4458. doi: 10.1126/scitranslmed.adr4458

PubMed Abstract | Crossref Full Text | Google Scholar

120. Jia M, Yue X, Sun W, Zhou Q, Chang C, Gong W, et al. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Sci Adv. (2023) 9:eadg4993. doi: 10.1126/sciadv.adg4993

PubMed Abstract | Crossref Full Text | Google Scholar

121. Li Z, Guo Z, Yang Z, Yang B, Hu Y, Xie X, et al. Metabolite-dependent m6A methylation driven by mechanotransduction-metabolism-epitranscriptomics axis promotes bone development and regeneration. Cell Rep. (2025) 44:115611. doi: 10.1016/j.celrep.2025.115611

PubMed Abstract | Crossref Full Text | Google Scholar

122. Nabavi N, Urukova Y, Cardelli M, JE A, and Harrison RE. Lysosome dispersion in osteoblasts accommodates enhanced collagen production during differentiation. J Biol Chem. (2008) 283:19678–90. doi: 10.1074/jbc.M802517200

PubMed Abstract | Crossref Full Text | Google Scholar

123. Micheletti C, Shah FA, Palmquist A, and Grandfield K. Ultrastructure and nanoporosity of human bone shown with correlative on-axis electron and spectroscopic tomographies. ACS Nano. (2023) 17:24710–24. doi: 10.1021/acsnano.3c04633

PubMed Abstract | Crossref Full Text | Google Scholar

124. Wen Z, Li S, Qiu H, Liu X, You Z, Yan Y, et al. Aligned nanofibers in biomimetic periosteal extracellular matrix/poly(ϵ-caprolactone) membranes enhance bone regeneration via the ITGB1/PI3K/AKT pathway. Regener Biomater. (2025) 12:rbaf099. doi: 10.1093/rb/rbaf099

PubMed Abstract | Crossref Full Text | Google Scholar

125. Dede Eren A, Lucassen AWA, Tuvshindorj U, Truckenmüller R, Giselbrecht S, Eren ED, et al. Cells dynamically adapt to surface geometry by remodeling their focal adhesions and actin cytoskeleton. Front Cell Dev Biol. (2022) 10:863721. doi: 10.3389/fcell.2022.863721

PubMed Abstract | Crossref Full Text | Google Scholar

126. Kanchanawong P and Calderwood DA. Organization, dynamics and mechanoregulation of integrin-mediated cell-ECM adhesions. Nat Rev Mol Cell Biol. (2023) 24:142–61. doi: 10.1038/s41580-022-00531-5

PubMed Abstract | Crossref Full Text | Google Scholar

127. Legerstee K and Houtsmuller AB. A layered view on focal adhesions. Biol (Basel). (2021) 10:1189. doi: 10.3390/biology10111189

PubMed Abstract | Crossref Full Text | Google Scholar

128. Khalil AA, Smits D, Haughton PD, Koorman T, Jansen KA, Verhagen MP, et al. A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion. Nat Commun. (2024) 15:4866. doi: 10.1038/s41467-024-49230-z

PubMed Abstract | Crossref Full Text | Google Scholar

129. Wen D, Gao Y, Liu Y, Ho C, Sun J, Huang L, et al. Matrix stiffness-induced α-tubulin acetylation is required for skin fibrosis formation through activation of Yes-associated protein. MedComm (2020). (2023) 4:e319. doi: 10.1002/mco2.319

PubMed Abstract | Crossref Full Text | Google Scholar

130. Wang B, He W, Prosseda PP, Li L, Kowal TJ, Alvarado JA, et al. OCRL regulates lysosome positioning and mTORC1 activity through SSX2IP-mediated microtubule anchoring. EMBO Rep. (2021) 22:e52173. doi: 10.15252/embr.202052173

PubMed Abstract | Crossref Full Text | Google Scholar

131. Wang K, Ho C, Li X, Hou J, Luo Q, Wu J, et al. Matrix stiffness regulates mitochondria-lysosome contacts to modulate the mitochondrial network, alleviate the senescence of MSCs. Cell Prolif. (2025) 58:e13746. doi: 10.1111/cpr.13746

PubMed Abstract | Crossref Full Text | Google Scholar

132. Ren WW, Kawahara R, Suzuki KGN, Dipta P, Yang G, Thaysen-Andersen M, et al. MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation. J Cell Biol. (2025) 224:e202407068. doi: 10.1083/jcb.202407068

PubMed Abstract | Crossref Full Text | Google Scholar

133. Li K and Jan YN. Experimental tools and emerging principles of organellar mechanotransduction. Trends Cell Biol. (2025) 35:944–54. doi: 10.1016/j.tcb.2024.12.011

PubMed Abstract | Crossref Full Text | Google Scholar

134. Daga P, Thurakkal B, Rawal S, and Das T. Matrix stiffening promotes perinuclear clustering of mitochondria. Mol Biol Cell. (2024) 35:ar91. doi: 10.1091/mbc.E23-04-0139

PubMed Abstract | Crossref Full Text | Google Scholar

135. Zaszczyńska A, Zabielski K, Gradys A, Kowalczyk T, and Sajkiewicz P. Piezoelectric scaffolds as smart materials for bone tissue engineering. Polymers (Basel). (2024) 16:2797. doi: 10.3390/polym16192797

PubMed Abstract | Crossref Full Text | Google Scholar

136. Ni X, Cui Y, Salehi M, Nai MLS, Zhou K, Vyas C, et al. Piezoelectric biomaterials for bone regeneration: roadmap from dipole to osteogenesis. Adv Sci (Weinh). (2025) 12:e14969. doi: 10.1002/advs.202414969

PubMed Abstract | Crossref Full Text | Google Scholar

137. Leppik L, Oliveira KMC, Bhavsar MB, and Barker JH. Electrical stimulation in bone tissue engineering treatments. Eur J Trauma Emerg Surg. (2020) 46:231–44. doi: 10.1007/s00068-020-01324-1

PubMed Abstract | Crossref Full Text | Google Scholar

138. Kao FC, Chiu PY, Tsai TT, and Lin ZH. The application of nanogenerators and piezoelectricity in osteogenesis. Sci Technol Adv Mater. (2019) 20:1103–17. doi: 10.1080/14686996.2019.1693880

PubMed Abstract | Crossref Full Text | Google Scholar

139. Zaszczyńska A, Zychowicz M, Kołbuk D, Denis P, Gradys A, and Sajkiewicz PŁ. On the structural and biological effects of hydroxyapatite and gold nano-scale particles in poly(Vinylidene fluoride) smart scaffolds for bone and neural tissue engineering. Molecules. (2025) 30:1041. doi: 10.3390/molecules30051041

PubMed Abstract | Crossref Full Text | Google Scholar

140. Wang B, Li G, Zhu Q, Liu W, Ke W, Hua W, et al. Bone repairment via mechanosensation of piezo1 using wearable pulsed triboelectric nanogenerator. Small. (2022) 18:e2201056. doi: 10.1002/smll.202201056

PubMed Abstract | Crossref Full Text | Google Scholar

141. Li Y, Fan Y, Zhao S, and Cheng B. Ultrasound-triggered piezoelectric polyetheretherketone with boosted osteogenesis via regulating Akt/GSK3β/β-catenin pathway. J Nanobiotechnology. (2024) 22:539. doi: 10.1186/s12951-024-02814-9

PubMed Abstract | Crossref Full Text | Google Scholar

142. Panwar P, Olesen JB, Delaisse JM, Søe K, and Brömme D. Cathepsin K inhibitors promote osteoclast-osteoblast communication and engagement of osteogenesis. JBMR Plus. (2025) 9:ziaf079. doi: 10.1093/jbmrpl/ziaf079

PubMed Abstract | Crossref Full Text | Google Scholar

143. Yang C, Tao H, Zhang H, Xia Y, Bai J, Ge G, et al. TET2 regulates osteoclastogenesis by modulating autophagy in OVX-induced bone loss. Autophagy. (2022) 18:2817–29. doi: 10.1080/15548627.2022.2048432

PubMed Abstract | Crossref Full Text | Google Scholar

144. Zhu G, Chen W, Tang CY, McVicar A, Edwards D, Wang J, et al. Knockout and Double Knockout of Cathepsin K and Mmp9 reveals a novel function of Cathepsin K as a regulator of osteoclast gene expression and bone homeostasis. Int J Biol Sci. (2022) 18:5522–38. doi: 10.7150/ijbs.72211

PubMed Abstract | Crossref Full Text | Google Scholar

145. Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int. (2015) 26:699–712. doi: 10.1007/s00198-014-2944-6

PubMed Abstract | Crossref Full Text | Google Scholar

146. Recker R, Dempster D, Langdahl B, Giezek H, Clark S, Ellis G, et al. Effects of odanacatib on bone structure and quality in postmenopausal women with osteoporosis: 5-year data from the phase 3 long-term odanacatib fracture trial (LOFT) and its extension. J Bone Miner Res. (2020) 35:1289–99. doi: 10.1002/jbmr.3994

PubMed Abstract | Crossref Full Text | Google Scholar

147. Stone JA, McCrea JB, Witter R, Zajic S, and Stoch SA. Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis. Br J Clin Pharmacol. (2019) 85:1072–83. doi: 10.1111/bcp.13869

PubMed Abstract | Crossref Full Text | Google Scholar

148. Drake MT, Clarke BL, Oursler MJ, and Khosla S. Cathepsin K inhibitors for osteoporosis: biology, potential clinical utility, and lessons learned. Endocr Rev. (2017) 38:325–50. doi: 10.1210/er.2015-1114

PubMed Abstract | Crossref Full Text | Google Scholar

149. Kozawa E, Cheng XW, Urakawa H, Arai E, Yamada Y, Kitamura S, et al. Increased expression and activation of cathepsin K in human osteoarthritic cartilage and synovial tissues. J Orthop Res. (2016) 34:127–34. doi: 10.1002/jor.23005

PubMed Abstract | Crossref Full Text | Google Scholar

150. Nagase S, Hashimoto Y, Small M, Ohyama M, Kuwayama T, and Deacon S. Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO-5334 after ascending single doses in post menopausal women. Br J Clin Pharmacol. (2012) 74:959–70. doi: 10.1111/j.1365-2125.2012.04307.x

PubMed Abstract | Crossref Full Text | Google Scholar

151. Tanaka M, Hashimoto Y, Hasegawa C, Deacon S, and Eastell R. Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis. BMC Musculoskelet Disord. (2017) 18:267. doi: 10.1186/s12891-017-1625-y

PubMed Abstract | Crossref Full Text | Google Scholar

152. Terawaki S, Camosseto V, Prete F, Wenger T, Papadopoulos A, Rondeau C, et al. RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4. J Cell Biol. (2015) 210:1133–52. doi: 10.1083/jcb.201501059

PubMed Abstract | Crossref Full Text | Google Scholar

153. Barnea-Zohar M, Stein M, Reuven N, Winograd-Katz S, Lee S, Addadi Y, et al. SNX10 regulates osteoclastogenic cell fusion and osteoclast size in mice. J Bone Miner Res. (2024) 39:1503–17. doi: 10.1093/jbmr/zjae125

PubMed Abstract | Crossref Full Text | Google Scholar

154. Aker M, Rouvinski A, Hashavia S, Ta-Shma A, Shaag A, Zenvirt S, et al. An SNX10 mutation causes Malignant osteopetrosis of infancy. J Med Genet. (2012) 49:221–6. doi: 10.1136/jmedgenet-2011-100520

PubMed Abstract | Crossref Full Text | Google Scholar

155. Bug DS, Barkhatov IM, Gudozhnikova YV, Tishkov AV, Zhulin IB, and Petukhova NV. Identification and characterization of a novel CLCN7 variant associated with osteopetrosis. Genes (Basel). (2020) 11:1242. doi: 10.3390/genes11111242

PubMed Abstract | Crossref Full Text | Google Scholar

156. Barvencik F, Kurth I, Koehne T, Stauber T, Zustin J, Tsiakas K, et al. CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals. J Bone Miner Res. (2014) 29:982–91. doi: 10.1002/jbmr.2100

PubMed Abstract | Crossref Full Text | Google Scholar

157. Gentner B, Tucci F, Galimberti S, Fumagalli F, De Pellegrin M, Silvani P, et al. Hematopoietic stem- and progenitor-cell gene therapy for hurler syndrome. N Engl J Med. (2021) 385:1929–40. doi: 10.1056/NEJMoa2106596

PubMed Abstract | Crossref Full Text | Google Scholar

158. Yang C and Wang X. Lysosome biogenesis: Regulation and functions. J Cell Biol. (2021) 220:e202102001. doi: 10.1083/jcb.202102001

PubMed Abstract | Crossref Full Text | Google Scholar

159. Ravazzano L, Colaianni G, Tarakanova A, Xiao YB, Grano M, and Libonati F. Multiscale and multidisciplinary analysis of aging processes in bone. NPJ Aging. (2024) 10:28. doi: 10.1038/s41514-024-00156-2

PubMed Abstract | Crossref Full Text | Google Scholar

160. Chen CG and Iozzo RV. Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth. Open Biol. (2022) 12:210304. doi: 10.1098/rsob.210304

PubMed Abstract | Crossref Full Text | Google Scholar

161. Wang C, Liu D, Zhang C, Sun J, Feng W, Liang XJ, et al. Defect-related luminescent hydroxyapatite-enhanced osteogenic differentiation of bone mesenchymal stem cells via an ATP-induced cAMP/PKA pathway. ACS Appl Mater Interfaces. (2016) 8:11262–71. doi: 10.1021/acsami.6b01103

PubMed Abstract | Crossref Full Text | Google Scholar

162. Zhang F, Wang Y, Zhang L, Wang C, Chen D, Liu H, et al. The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence. Elife. (2025) 13:RP101984. doi: 10.7554/eLife.101984

PubMed Abstract | Crossref Full Text | Google Scholar

163. Fernandes MH, Alves MM, Cebotarenco M, Ribeiro IAC, Grenho L, Gomes PS, et al. Citrate zinc hydroxyapatite nanorods with enhanced cytocompatibility and osteogenesis for bone regeneration. Mater Sci Eng C Mater Biol Appl. (2020) 115:111147. doi: 10.1016/j.msec.2020.111147

PubMed Abstract | Crossref Full Text | Google Scholar

164. Zhang B, Hou R, Zou Z, Luo T, Zhang Y, Wang L, et al. Mechanically induced autophagy is associated with ATP metabolism and cellular viability in osteocytes in vitro. Redox Biol. (2018) 14:492–8. doi: 10.1016/j.redox.2017.10.021

PubMed Abstract | Crossref Full Text | Google Scholar

165. Xia X, Kar R, Gluhak-Heinrich J, Yao W, Lane NE, Bonewald LF, et al. Glucocorticoid-induced autophagy in osteocytes. J Bone Miner Res. (2010) 25:2479–88. doi: 10.1002/jbmr.160

PubMed Abstract | Crossref Full Text | Google Scholar

166. Jia J, Yao W, Guan M, Dai W, Shahnazari M, Kar R, et al. Glucocorticoid dose determines osteocyte cell fate. FASEB J. (2011) 25:3366–76. doi: 10.1096/fj.11-182519

PubMed Abstract | Crossref Full Text | Google Scholar

167. Yin X, Zhou C, Li J, Liu R, Shi B, Yuan Q, et al. Autophagy in bone homeostasis and the onset of osteoporosis. Bone Res. (2019) 7:28. doi: 10.1038/s41413-019-0058-7. Regener Biomater. (2025) 12:rbaf028. doi: 10.1093/rb/rbaf028

PubMed Abstract | Crossref Full Text | Google Scholar

168. Yuze M, Hu J, Jun L, Cheng X, Tianwen X, and Junqiang Z. Osteocytes function as biomechanical signaling hubs bridging mechanical stress sensing and systemic adaptation. Front Physiol. (2025) 16:1629273. doi: 10.3389/fphys.2025.1629273

PubMed Abstract | Crossref Full Text | Google Scholar

169. Karthik V and Guntur AR. Energy metabolism of osteocytes. Curr Osteoporos Rep. (2021) 19:444–51. doi: 10.1007/s11914-021-00688-6

PubMed Abstract | Crossref Full Text | Google Scholar

170. Mao L, Wang L, Xu J, and Zou J. The role of integrin family in bone metabolism and tumor bone metastasis. Cell Death Discov. (2023) 9:119. doi: 10.1038/s41420-023-01417-x

PubMed Abstract | Crossref Full Text | Google Scholar

171. Ratcliffe CD, Sahgal P, Parachoniak CA, Ivaska J, and Park M. Regulation of cell migration and β1 integrin trafficking by the endosomal adaptor GGA3. Traffic. (2016) 17:670–88. doi: 10.1111/tra.12390

PubMed Abstract | Crossref Full Text | Google Scholar

172. Hofbauer LC, Baschant U, and Hofbauer C. Targeting senescent cells to boost bone fracture healing. J Clin Invest. (2024) 134:e181974. doi: 10.1172/JCI181974

PubMed Abstract | Crossref Full Text | Google Scholar

173. Chen C, Zhang Z, Liu C, Sun P, Liu P, and Li X. ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis. Cell Metab. (2024) 36:498–510.e11. doi: 10.1016/j.cmet.2023.12.015

PubMed Abstract | Crossref Full Text | Google Scholar

174. Meizlish ML, Kimura Y, Pope SD, Matta R, Kim C, Philip NH, et al. Mechanosensing regulates tissue repair program in macrophages. Sci Adv. (2024) 10:eadk6906. doi: 10.1126/sciadv.adk6906

PubMed Abstract | Crossref Full Text | Google Scholar

175. Sakai E, Saito M, Koyanagi Y, Takayama Y, Farhana F, Yamaguchi Y, et al. Autophagy regulator rufy 4 promotes osteoclastic bone resorption by orchestrating cytoskeletal organization via its RUN domain. Cells. (2024) 13:1766. doi: 10.3390/cells13211766

PubMed Abstract | Crossref Full Text | Google Scholar

176. Mukherjee K and Chattopadhyay N. Pharmacological inhibition of cathepsin K: A promising novel approach for postmenopausal osteoporosis therapy. Biochem Pharmacol. (2016) 117:10–9. doi: 10.1016/j.bcp.2016.04.010

PubMed Abstract | Crossref Full Text | Google Scholar

177. Zhang X, Luo Y, Hao H, Krahn JM, Su G, Dutcher R, et al. Heparan sulfate selectively inhibits the collagenase activity of cathepsin K. Matrix Biol. (2024) 129:15–28. doi: 10.1016/j.matbio.2024.03.005

PubMed Abstract | Crossref Full Text | Google Scholar

178. Moon DO. Review of cathepsin K inhibitor development and the potential role of phytochemicals. Molecules. (2024) 30:91. doi: 10.3390/molecules30010091

PubMed Abstract | Crossref Full Text | Google Scholar

179. Li M, Yang D, Yan H, Tang Z, Jiang D, Zhang J, et al. Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption. Dev Cell. (2022) 57:2365–2380.e8. doi: 10.1016/j.devcel.2022.09.013

PubMed Abstract | Crossref Full Text | Google Scholar

180. Ostertag A, Léger B, Koumakis E, Fardellone P, Zarka M, Funck-Brentano T, et al. Impaired organic and mineral extracellular matrix composition in early-onset osteoporosis. J Bone Miner Res doi: 10.1093/jbmr/zjaf159

PubMed Abstract | Crossref Full Text | Google Scholar

181. Mitra D, Yasui OW, Harvestine JN, Link JM, Hu JC, Athanasiou KA, et al. Exogenous lysyl oxidase-like 2 and perfusion culture induce collagen crosslink formation in osteogenic grafts. Biotechnol J. (2019) 14:e1700763. doi: 10.1002/biot.201700763

PubMed Abstract | Crossref Full Text | Google Scholar

182. Li C and Wang L. TFEB-dependent autophagy is involved in scavenger receptor OLR1/LOX-1-mediated tumor progression. Autophagy. (2022) 18:462–4. doi: 10.1080/15548627.2021.2012970

PubMed Abstract | Crossref Full Text | Google Scholar

183. An S, Wang D, Ma X, and Liu C. Whole body vibration remodels skeletal muscle via autophagy and energy metabolism in diabetic mice. Mol Med Rep. (2022) 25:182. doi: 10.3892/mmr.2022.12698

PubMed Abstract | Crossref Full Text | Google Scholar

184. Kureel SK, Maroto R, Aniqua M, Powell S, Singh E, Margadant F, et al. Rejuvenation of senescent cells, in vitro and in vivo, by low-frequency ultrasound. Aging Cell. (2025) 24:e70008. doi: 10.1111/acel.70008

PubMed Abstract | Crossref Full Text | Google Scholar

185. Wu Y, Sun B, Tang Y, Shen A, Lin Y, Zhao X, et al. Bone targeted nano-drug and nano-delivery. Bone Res. (2024) 12:51. doi: 10.1038/s41413-024-00356-2

PubMed Abstract | Crossref Full Text | Google Scholar

186. Liang M, Zhou L, Li J, Liang B, Zhou L, Xue F, et al. An acid-responsive bone-targeting nanoplatform loaded with curcumin balances osteogenic and osteoclastic functions. Regener Biomater. (2025) 12:rbaf028. doi: 10.1093/rb/rbaf028

PubMed Abstract | Crossref Full Text | Google Scholar