Osteoporosis (OP) is a systemic skeletal disorder resulting from impaired bone remodeling, and is characterized by decreased bone mass, the deterioration of bone microarchitecture and an enhanced risk of fragility fractures (1). This disease arises from an imbalance between osteoclast-mediated bone resorption and osteoblast-driven bone formation, resulting in the progressive development of skeletal fragility and notable morbidity, particularly in older adults (2,3). As population aging continues worldwide, OP remains a notable public health challenge because of its association with increased fracture risk, disability, reduced patient quality of life and increased healthcare burden (4). Despite the availability of antiresorptive and anabolic therapies, numerous patients with OP continue to experience suboptimal therapeutic responses or adverse effects during treatment, underscoring the requirement for improved understanding of the molecular mechanisms governing bone homeostasis (5).

Bone remodeling is coordinated through dynamic interactions among osteoblasts, osteoclasts, osteocytes, endothelial cells, immune cells and the extracellular matrix (ECM) (6). A previous study suggests that ECM-cell communication plays a role in maintaining skeletal integrity, with integrins serving as key mediators that couple extracellular mechanical and biochemical cues to intracellular responses (7). Among members of the integrin family, integrin αVβ3 has emerged as an important regulator of bone homeostasis due to its broad expression in multiple bone-associated cell types and its ability to integrate signaling pathways involved in cellular adhesion, migration, mechanotransduction, survival and differentiation (8). Through interactions with ECM proteins containing the Arg-Gly-Asp (RGD) motif, integrin αVβ3 has been shown to coordinate multiple biological processes that collectively influence bone remodeling (9).

Accumulating experimental evidence has indicated that integrin αVβ3 participates in several interconnected aspects of skeletal biology. In osteoclasts, integrin αVβ3 has been shown to regulate cytoskeletal organization, adhesion to the bone surface, migration and bone-resorptive activity (10). In osteoblasts and bone marrow mesenchymal stem cells (BMSCs), integrin αVβ3 has been shown to contribute to osteogenic differentiation and mechanosensitive signaling through pathways involving focal adhesion kinase (FAK), PI3K/AKT, MAPK and Wnt-associated signaling (11–13). A study further demonstrated that integrin αVβ3 influences osteocyte-mediated mechanotransduction, angiogenesis within the bone microenvironment, inflammatory signaling and estrogen-associated skeletal adaptation (14). Notably, as discussed in the subsequent sections on osteoblasts, osteoclasts, osteocytes and the estrogen-deficient bone microenvironment, the functions of integrin αVβ3 appear to vary according to cell type and microenvironmental context, suggesting that αVβ3 may function as a multifunctional signaling node rather than as a uniformly beneficial or detrimental regulator of bone homeostasis (15).

Although studies have investigated the individual functions of integrin αVβ3 in specific bone cell populations, current knowledge remains fragmented and, to the best of our knowledge, the interplay among its diverse biological roles has not been comprehensively integrated and critically evaluated in relation to OP pathogenesis (16,17). In particular, the mechanisms by which integrin αVβ3 coordinates communication between pathways for bone remodeling, mechanotransduction, angiogenesis, inflammatory regulation and estrogen signaling remain incompletely elucidated. Furthermore, the context-dependent nature of integrin αVβ3 signaling has important implications for targeted therapy, highlighting the need to carefully evaluate therapeutic strategies that modulate αVβ3 activity (18–23).

The present review systematically summarizes current evidence regarding the molecular mechanisms involved in the integrin αVβ3-mediated regulation of bone homeostasis, with particular emphasis on its roles in osteoblasts, osteoclasts, osteocytes, angiogenesis, inflammation and estrogen-associated skeletal remodeling. The present review also: i) Discusses the context-dependent functions of integrin αVβ3 in OP pathogenesis; ii) critically evaluates the current evidence supporting integrin αVβ3-targeted therapeutic approaches; and iii) highlights the major challenges and future research directions required for the clinical translation of such therapies.

Bone homeostasis is maintained by the continuous remodeling of bone, in which osteoblast-mediated bone formation and osteoclast-mediated bone resorption are coordinated by osteocytes, ECM cues, vascular signals and immune mediators (24). Disruption of this coupling contributes to progressive bone loss and OP (25). Fig. 1 summarizes the coordinated roles of osteoblasts, osteoclasts and osteocytes, together with the principal signaling mediators that regulate bone formation and resorption. Since integrin αVβ3 is expressed in several skeletal and bone-associated cell populations, a concise overview of the cellular bone-remodeling network is necessary to fully elucidate its functions in a biological context (26,27).

Osteoblasts arise from BMSCs and are responsible for bone mineralization and ECM synthesis. Their differentiation is regulated by osteogenic transcription factors, including runt-related transcription factor 2 (RUNX2) and osterix (OSX), as well as signaling via the bone morphogenetic protein (BMP), Wnt/β-catenin and growth factor signaling pathways (28,29). Osteoblasts also influence osteoclastogenesis through the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) axis, thereby linking bone formation to resorption (30). Within the context of OP, integrin αVβ3-mediated cell adhesion and mechanotransduction have been shown to modulate osteoblast differentiation and matrix-responsive signaling (31,32).

Osteoclasts are multinucleated cells of hematopoietic origin whose differentiation depends primarily on macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) signaling. Mature osteoclasts attach to the mineralized bone surface, organize specialized cytoskeletal structures and resorb the bone matrix through acid-mediated mineral dissolution and proteolytic degradation of its organic components (33). Integrin αVβ3 is particularly relevant in osteoclasts because its recognition of RGD-containing ECM proteins supports adhesion, migration and cytoskeletal polarization, thereby facilitating formation of the actin-rich sealing zone required to establish the resorption compartment and enable efficient bone resorption (34,35). These functions provide the strongest mechanistic basis for considering integrin αVβ3 as a therapeutic target in OP-associated bone loss.

Osteocytes are terminally differentiated cells that are derived from the osteoblast cell lineage; these cells are embedded within the mineralized bone matrix and serve as important mechanosensors within the bone tissue. Through their lacuna-canalicular network, these cells regulate both osteoblast and osteoclast activity by modulating sclerostin, dickkopf-1, RANKL, OPG, nitric oxide and ATP signaling (36,37). Integrin αVβ3 has been shown to contribute to osteocyte-mediated mechanotransduction and may therefore influence how mechanical loads are translated into adaptive bone remodeling responses. This role is particularly relevant under estrogen-deficient conditions, in which impaired αVβ3-mediated mechanosensation in osteocytes has been associated with altered focal adhesion organization, an increased RANKL/OPG ratio and reduced cyclooxygenase-2 (COX-2) responses to mechanical stimulation (38).

Bone lining cells, which are osteoblast-lineage cells located on quiescent bone surfaces, including the endosteal surface, also contribute to local bone remodeling through ECM turnover and regulation of the RANKL/OPG axis (39). However, direct evidence defining integrin αVβ3-specific functions in endosteal cells remains limited. Bone lining cells contribute to the local remodeling microenvironment through interactions with the bone matrix and paracrine regulation of neighboring bone cells. Although αVβ3-specific functions in bone lining cells remain insufficiently characterized and are therefore not discussed further in the present review, these cells are included here to provide the cellular context in which bone remodeling occurs. Bone remodeling depends on coordinated interactions among osteoblasts, osteoclasts, osteocytes and other cells within the local microenvironment. Within this multicellular system, αVβ3 functions in a cell type- and context-dependent manner, contributing to ECM recognition, cytoskeletal organization and mechanotransduction in different skeletal cell populations (40). This framework provides the basis for the more detailed mechanistic discussion of integrin αVβ3 activity in the following sections.

Integrins are heterodimeric transmembrane receptors that facilitate bidirectional communication between cells and the ECM, thereby regulating cellular adhesion, migration, mechanotransduction, survival and differentiation. In mammals, 18 α and 8 β subunits assemble into 24 distinct integrin heterodimers with different ligand-binding properties. Ligand recognition is determined by the extracellular domains of the αβ heterodimer, whereas the β-subunit cytoplasmic tail has a prominent role in recruiting cytoskeletal and adaptor proteins involved in intracellular signaling (41–43).

Among members of the integrin family, integrin αVβ3 belongs to the RGD-binding subfamily and recognizes ECM proteins containing the RGD motif, including vitronectin, osteopontin (OPN), fibronectin and bone sialoprotein (44). Ligand binding induces conformational activation and receptor clustering, which promotes the assembly of focal adhesion complexes and recruitment of adaptor and signaling proteins, including FAK and Src, thereby enabling integrin αVβ3 to couple extracellular biochemical and mechanical cues to intracellular signaling pathways (45). Consequently, integrin αVβ3 is able to regulate diverse cellular processes, including adhesion, migration, proliferation, survival and mechanotransduction, through signaling networks involving FAK, Src family kinase, the PI3K/AKT signaling pathway, MAPK and Rho GTPases (46–49). These signaling events enable cells to continuously sense and respond to changes in their extracellular microenvironment (50).

Structurally, integrin αVβ3 is a heterodimeric glycoprotein composed of non-covalently associated αV and β3 subunits (Fig. 2A). The αV subunit contains: i) A β-propeller domain; ii) a thigh domain; iii) two calf domains; iv) a transmembrane helix; and v) a short cytoplasmic tail. On the other hand, the β3 subunit consists of: i) A βI domain; ii) a hybrid domain; iii) a plexin-semaphorin-integrin domain; iv) four epidermal growth factor-like repeats; v) a β-tail domain; vi) a transmembrane helix; and vii) a cytoplasmic tail (51,52). The ligand-binding interface of integrin αVβ3 is formed by the β-propeller domain of the αV subunit together with the βI domain of the β3 subunit. The β3 βI domain contains three divalent metal ion-binding sites: The metal ion-dependent adhesion site (MIDAS), the adjacent to MIDAS and the ligand-associated metal-binding site (also termed the synergistic metal ion-binding site). These sites contribute to ligand binding and its regulation, with the MIDAS metal ion directly coordinating the Asp residue of RGD-containing ligands (53,54).

Similar to other integrins, integrin αVβ3 undergoes dynamic conformational transitions among three major states: i) A bent-closed conformation associated with low ligand affinity; ii) an extended-closed conformation that generally retains low ligand affinity; and iii) an extended-open conformation associated with high ligand affinity. These conformational transitions are coupled to bidirectional inside-out and outside-in signaling mechanisms (Fig. 2B) (55). During inside-out signaling, intracellular adaptor proteins, particularly talin and kindlin, bind to the cytoplasmic tail of the β3 subunit, inducing conformational changes that increase ligand-binding affinity (53). Following ligand engagement, outside-in signaling promotes receptor clustering and the assembly of focal adhesion complexes, involving proteins such as FAK, Src, paxillin and vinculin, which activate downstream pathways regulating cytoskeletal organization, gene transcription and other cellular responses to the extracellular environment (56–58).

Within the skeletal system, integrin αVβ3 is expressed in multiple bone-associated cell populations, including osteoclasts, osteoblasts, osteocytes, endothelial cells and several immune cell types. Through interactions with ECM components, integrin αVβ3 contributes to adhesion and cytoskeletal organization in osteoclasts, differentiation and mechanosensitive signaling in osteoblast-lineage cells, mechanotransduction in osteocytes, angiogenic signaling in endothelial cells and inflammatory signaling in immune and stromal cells (59,60). For example, inhibition of integrin αVβ3 has been shown to attenuate mechanosensitive calcium signaling in osteocytes and to impair mechanically induced COX-2 expression and prostaglandin E2 (PGE2) release. Because COX-2 induction and PGE2 production are established biochemical responses of osteocytes to mechanical stimulation, these findings support the involvement of αVβ3 in coupling mechanical cues to downstream cellular signaling (61). In addition, integrin αVβ3 exhibits functional crosstalk with growth factor receptors, including EGFR and transforming growth factor-β receptor II, thereby coordinating signaling pathways, such as the Ras/MEK/MAPK, PI3K/AKT and RhoA/Rho-associated protein kinase pathways, which influence cell migration, proliferation and survival (62–64).

Collectively, evidence from osteoclast and osteocyte studies indicates that integrin αVβ3 links ECM interactions to intracellular signaling in multiple bone cell populations. Its biological effects are cell type- and context-dependent, reflecting differences in ECM ligand availability, mechanical stimulation and local hormonal or inflammatory conditions. These factors represent components of the local bone microenvironment that can modify αVβ3 expression, activation and downstream signaling. This context dependence may contribute to the diverse functions of αVβ3 in bone remodeling and OP (65,66).

The functional effects of integrin αVβ3 in bone remodeling arise from the coordinated activity of the αVβ3 heterodimer. Although the αV and β3 subunits make distinct structural and signaling contributions, ligand recognition and signal transmission depend on their assembly as a functional receptor. In αVβ3, the extracellular domains of both subunits contribute to ligand binding, whereas the β3 cytoplasmic domain has a prominent role in recruiting intracellular adaptor and signaling proteins. These coordinated properties provide the basis for the cell type-specific effects of αVβ3 subsequently discussed in osteoblast-lineage cells, osteoclasts and osteocytes (67,68). Therefore, elucidating the complimentary roles of these subunits is key to understanding how integrin αVβ3 affects bone remodeling.

The primary function of the αV subunit is to facilitate recognition of the ECM via interactions with RGD-containing ligands, such as fibronectin, vitronectin, OPN and bone sialoprotein (44). Such interactions play important roles in mediating cell adhesion and transducing extracellular signals that regulate osteogenic differentiation and skeletal organization. Experimental evidence has shown that αV subunit-mediated signaling is involved in osteogenic differentiation by stimulating the activation of various signaling cascades, such as the BMP2/SMAD and ERK/STAT pathways, which induce the differentiation of BMSCs into osteoblasts (69,70). In addition to its involvement in bone development, the αV subunit, as part of the αVβ3 heterodimer, contributes to osteoclast attachment and migration through recognition of RGD-containing matrix ligands, including OPN and vitronectin. These interactions facilitate osteoclast adhesion and cytoskeletal organization required for subsequent bone resorption (71). The implication of these findings is that the αV subunit of integrin acts as an interface for bone cells in relation to the ECM during bone resorption and formation (72).

On the other hand, signaling within cells is mediated by the β3 integrin subunit after receptor-ligand binding. In osteoclasts, the interaction of the β3 subunit with molecules such as talin-1 and kindlin-3 is important for the activation of integrins and the formation of focal adhesions, which are necessary for cytoskeletal reorganization and cellular attachment to the bone matrix (73). β3 subunit-mediated intracellular signaling is characterized by the recruitment and activation of Src family kinases and focal adhesion-associated proteins, which interact with downstream signaling networks, including JNK and NF-κB pathways, to regulate osteoclast function (74). Further evidence indicates that β3-integrin signaling interacts with the microRNA-17 (miR-17)/osteoclastic protein-tyrosine phosphatase (PTP-oc)/ephrin type-A receptor 4 (EphA4) regulatory axis during osteoclast activation. In this axis, miR-17 negatively regulates PTP-oc expression, whereas PTP-oc activates Src signaling by dephosphorylating the inhibitory Tyr527 residue and suppresses the inhibitory signaling of EphA4. These interconnected mechanisms modulate β3-integrin signaling, cytoskeletal organization and osteoclast activity (34,75). Although these signal transduction pathways have been predominantly studied in osteoclasts, they have also been shown to serve roles in osteoclast-osteoblast communication during coupled bone remodeling (76,77).

Collectively, the biological functions of the αV and β3 subunits are best understood in the context of the functional αVβ3 heterodimer rather than as independent activities. Both subunits contribute to the extracellular ligand-binding interface, whereas the β3 cytoplasmic domain has a prominent role in recruiting adaptor and signaling proteins that transmit ligand-dependent signals to the cell interior (78). Skeletal and microenvironmental cell populations further indicate that the functional consequences of αVβ3 signaling vary according to cellular context. These include regulation of osteogenic and mechanosensitive responses in osteoblast-lineage cells and osteocytes, adhesion and cytoskeletal organization in osteoclasts, angiogenic signaling in endothelial cells and inflammatory responses in immune and stromal cells. Such effects may also be influenced by local factors, including ECM ligand availability, mechanical stimulation, hormonal status and inflammatory conditions. Thus, αVβ3 is more appropriately considered a context-dependent regulator of bone remodeling than a receptor that exerts a uniform biological effect across skeletal cell populations (79–81).

Although there are differences in the structure and signaling properties of the αV and β3 integrin subunits, their functional roles are merged through the binding of the integrin αVβ3 dimeric complex. It is therefore necessary to consider that the biological activities regulated by integrin αVβ3 that are described in the following sections, such as the differentiation of osteoblasts, osteoclast function, angiogenesis and bone microenvironmental signaling, represent the combined activity of both subunits of integrin αVβ3 (82).

Increasing numbers of scientific studies have supported the importance of integrin αVβ3 as an effective therapeutic target for OP because of the role of this integrin in several aspects of bone remodeling (158,159). Although traditional antiresorptive agents work on the basis of targeting osteoclasts, the modulation of integrin αVβ3 activity can have a notable impact on multiple signaling pathways associated with the maintenance of bone homeostasis. At the same time, the wide distribution of integrin αVβ3 in different types of tissue and its various roles in these tissues pose certain challenges for developing novel treatments for OP.

Evidence supporting integrin αVβ3 as a potential therapeutic target in OP is derived predominantly from preclinical studies using cellular and animal models. Pharmacological inhibition of αVβ3 has been shown to impair osteoclast adhesion and cytoskeletal organization, including disruption of actin-ring and sealing-zone formation, thereby reducing bone-resorptive activity (64,69,160). For example, HSA-ARLDDL, a highly selective αVβ3 antagonist, inhibited RANKL-induced osteoclast formation and attenuated cancellous bone loss in the tibia and femur of ovariectomized mice, while having no detectable effect on osteoblast differentiation or calcium deposition under the experimental conditions examined (69). In addition to direct αVβ3 antagonism, experimental inhibition of αVβ3-associated intracellular signaling components, particularly Pyk2 and Src, has been associated with disruption of osteoclast cytoskeletal organization, migration and resorptive function (64,161). Collectively, these preclinical findings identify αVβ3 and its associated signaling machinery as potential antiresorptive targets in conditions characterized by excessive osteoclast activity; however, their therapeutic efficacy, selectivity and safety in human OP remain to be established (1,162). Taken together, these studies provide evidence that the involvement of integrin αVβ3 in pathological bone resorption could be targeted for the treatment of conditions with excess osteoclastic activity.

Several approaches have since been employed to study the pharmacology of integrin αVβ3 signaling. Dual blockade of c-FMS and integrin αVβ3 has been shown to provide improved suppression of osteoclast differentiation compared with their individual blockade in preclinical models (141). This suggests that targeting multiple signal transduction pathways may be more effective therapeutically than targeting individual osteogenic pathways. Additionally, studies have shown promising results regarding the use of natural inhibitors. For example, tablysin-15 has been shown to block osteoclast differentiation predominantly through the inhibition of integrin αVβ3-induced activation of the FAK pathway, whereas cilengitide has been shown to prevent integrin αVβ3-dependent cell adhesion and bone resorption in osteoclasts (139,163). These results support the therapeutic efficacy of integrin αVβ3-targeting therapy to mitigate osteoclastic activity; however, additional research is required to establish the efficacy and safety of such therapies (160).

Clinical data for therapies targeting integrin αVβ3 remain relatively sparse. In a study by Murphy et al (140), administration of L-000845704, an inhibitor of integrin αVβ3, markedly decreased the levels of biochemical indicators of bone resorption and increased bone mineral density in postmenopausal women. Although these findings suggest potential therapeutic relevance, clinical evidence supporting integrin αVβ-targeted therapies remains limited. Adequately powered randomized controlled trials with longer follow-up periods are therefore required to determine their efficacy in reducing fracture risk and to establish their long-term safety. Therefore, integrin αVβ3-based approaches should be considered as investigational, rather than clinically proven therapies for OP.

Notably, the use of integrin αVβ3 as a target for OP therapy poses certain biological problems. Although targeting osteoclast-associated αVβ3 signaling may provide an approach to suppress excessive bone resorption, αVβ3 is not restricted to osteoclasts and is also expressed in osteoblast-lineage cells, osteocytes, endothelial cells, macrophages and other immune cell populations. Consequently, systemic αVβ3 inhibition may affect αVβ3-dependent functions in non-osteoclast cells, highlighting the importance of cell-selective targeting when developing αVβ3-directed therapies for bone disorders. Thus, systematic blockage may also affect various physiological processes outside of bone resorption. For example, as the role of integrin αVβ3 is important in endothelial cell function and angiogenesis, long-term inhibition may negatively affect vascular remodeling and tissue repair (160). Furthermore, since integrin αVβ3 is present in platelets and immune cells, there remains a potential risk that integrin αVβ3 inhibition may negatively affect immune function and wound healing, although this issue has not been extensively investigated in clinical trials for OP (93).

The challenges with targeting integrin αVβ3 also include the context-dependent nature of its activity. Experimental data have shown that the inhibition of integrin αVβ3 signaling leads to reduced osteoclast-mediated bone resorption (64,69). However, in the case of estrogen deficiency, study has shown that reduced integrin αVβ3 expression in osteocytes is associated with impaired mechanotransduction and notable bone loss (139). Despite their contradictory nature, these two observations may be explained by the fact that integrin αVβ3 serves different roles in distinct cells in the skeletal system (155). The skeletal effects of altered integrin β3/αVβ3 signaling appear to depend on the cell type and experimental context. In osteocytes, β3 integrin deletion impairs mechanotransduction and mechanically induced bone formation, whereas estrogen withdrawal alters αVβ3 localization at focal adhesions, disrupts mechanosensitive signaling and modifies the RANKL/OPG ratio (164,165). Additional factors that may contribute to differences among experimental findings include the cell population targeted, the use of global vs. cell type-specific genetic deletion, developmental or compensatory responses to gene deletion, the duration and severity of estrogen deficiency and differences between genetic, pharmacological and hormonal models. These variables should therefore be considered when interpreting apparently divergent effects of αVβ3/β3-integrin perturbation on bone homeostasis. Collectively, these observations support a cell type- and context-dependent role for integrin αVβ3 in skeletal homeostasis rather than a uniformly beneficial or detrimental effect on bone remodeling. Accordingly, therapeutic development should consider the distinct functions of αVβ3 across bone-associated cell populations rather than relying solely on systemic receptor blockade. Preclinical studies have demonstrated that selective αVβ3 antagonism can suppress osteoclast-mediated bone resorption and attenuate ovariectomy-induced bone loss (153,166). Future strategies aimed at improving therapeutic selectivity may include preferential targeting of osteoclast-associated αVβ3 signaling or selective modulation of downstream signaling components while preserving αVβ3-dependent functions in other skeletal cells. However, these more selective approaches remain largely investigational and require further experimental and clinical validation. Furthermore, advancements in the fields of spatial transcriptomics, single-cell multi-omics and conditional genetics will be important for elucidating the roles of integrin αVβ3 on a cell-specific level and identifying patients who would benefit the most from integrin αVβ3-targeted therapy.

Bone remodeling is a highly coordinated process that depends on continuous communication among osteoblasts, osteoclasts, osteocytes, endothelial cells, immune cells and the ECM. Throughout the present review, integrin αVβ3 has been highlighted as an important molecular interface linking ECM interactions with intracellular signaling pathways that collectively regulate skeletal homeostasis. Rather than functioning solely as an adhesion receptor, integrin αVβ3 integrates biochemical and mechanical signals to influence osteoblast differentiation, osteoclast activation, osteocyte-mediated mechanotransduction, angiogenesis and immune-skeletal interactions. These diverse biological functions position integrin αVβ3 as an important regulator of bone remodeling and contribute to its involvement in the pathogenesis of OP.

One of the most notable takeaways from previous research regarding the activity of integrin αVβ3 is that the biological effects of integrin αVβ3 are context-dependent. Experimental studies have indicated that integrin αVβ3 contributes to osteogenic differentiation through the coordinated regulation of focal adhesion signaling, cytoskeletal organization and mechanotransduction, while simultaneously facilitating osteoclast adhesion, migration and bone-resorptive activity through interactions with ECM ligands and RANKL-associated signaling pathways. In addition, integrin αVβ3 has been shown to participate in angiogenesis and osteoimmune communication by integrating endothelial, inflammatory and ECM-derived signals within the bone microenvironment. Notably, studies have indicated that the function of integrin αVβ3 differs among osteoblasts, osteoclasts, osteocytes, endothelial cells and immune cells, emphasizing that the biological activity of integrin αVβ3 should be interpreted with regards to its specific cellular and microenvironmental context, rather than considered as uniformly beneficial or detrimental in bone homeostasis.

Current evidence has also indicated that integrin αVβ3-targeting may offer potential as a novel treatment strategy for diseases associated with increased bone resorption. In one preclinical study, selective inhibition of integrin αVβ3 with HSA-ARLDDL suppressed RANKL-induced osteoclastogenesis and attenuated ovariectomy-induced cancellous bone loss, supporting the potential of αVβ3 as an antiresorptive therapeutic target in OP (69). However, clinical data supporting the efficacy and long-term safety of αVβ3-targeted therapies for OP remain limited, and the expression of αVβ3 across multiple cell types raises additional concerns regarding therapeutic specificity and potential off-target effects. As such, the effects of treatment on physiological angiogenesis, wound healing, immunomodulation and platelets need to be considered in the development of any novel drug that targets the integrin αVβ3 receptor. Thus, the selective modulation of integrin αVβ3 probably represents a more promising therapeutic option for the treatment of skeletal disorders than treatments involving all-out integrin αVβ3 blockade.

Although substantial progress has been made in understanding integrin αVβ3 signaling in bone, several important questions remain unresolved. First, the molecular mechanisms underlying the cell type-specific functions of αVβ3 require further clarification, particularly how αVβ3-dependent responses in osteoblasts, osteoclasts, osteocytes, endothelial cells and immune cells collectively influence intercellular communication during physiological and pathological bone remodeling. Second, the apparently divergent skeletal outcomes observed in β3-integrin genetic-deficiency and estrogen-deficiency models highlight the need to distinguish the effects of cell type-specific loss of β3/αVβ3 function from the broader effects of estrogen deficiency on osteoclast activity, osteocyte mechanotransduction and RANKL/OPG-mediated remodeling. Finally, although interactions between αVβ3 and signaling pathways including Wnt/β-catenin, BMP, PI3K/AKT, MAPK and RANKL/RANK have been described, their relative contributions, temporal coordination and cell type-specific integration during bone remodeling remain incompletely understood. Defining these context-dependent signaling relationships will be important for determining when and in which cellular compartments αVβ3 represents an appropriate therapeutic target. Therefore, future research should focus on the application of sophisticated experimental techniques that can elucidate the complex spatiotemporal nature of the integrin αVβ3 signaling pathway in bone remodeling. Techniques such as conditional cell-specific knockout studies, lineage tracing, spatial omics, single cell multi-omics and intravital imaging may contribute to an improved understanding of the processes involved in integrin αVβ3 signaling in the bone microenvironment. Simultaneously, the generation of selective drug delivery systems, allosteric modulators and combinatorial therapies may help to enhance the therapeutic potential of integrin αVβ3-targeting while maintaining the physiological role of integrin αVβ3 outside of skeletal tissues.

In conclusion, current evidence indicates that integrin αVβ3 contributes to bone remodeling by coupling interactions with ECM ligands to intracellular signaling that regulates cell adhesion, cytoskeletal organization, mechanotransduction and other cell type-specific responses in bone-associated cells. Its functional consequences vary among osteoclasts, osteoblast-lineage cells, osteocytes, endothelial cells and immune cells and depend on the local signaling and microenvironmental context. Although substantial progress has been made in defining these functions, important questions remain regarding the molecular determinants of cell type-specific αVβ3 signaling, its integration with other bone-remodeling pathways and the consequences of selectively modulating this receptor in different skeletal cell populations. Addressing these knowledge gaps will improve understanding of αVβ3-dependent mechanisms in OP and help determine whether cell-selective or pathway-specific modulation of αVβ3 can be translated into safe and effective therapeutic strategies for OP and other disorders characterized by abnormal bone remodeling.