Rheumatoid arthritis (RA) is a complex disease characterized by chronic synovial inflammation, progressive joint destruction, and systemic autoimmune response (1), with a global prevalence of approximately 0.5 to 1% (2). One of the main pathological features leads to joint bone destruction, which seriously affects patients’ joint function and quality of life (3). Actually, osteoclast (OC)-mediated bone erosion is a key link in joint destruction. RA bone metabolism is regulated by a variety of cells, and recent studies have shown that (4, 5), the nature of the abnormalities of RA bone metabolism is the result of the cytokine-mediated regulation of the bone metabolism of immune and non-immune cells. The imbalance of bone metabolism caused by abnormal OC differentiation leads to localized joint bone erosion and destruction. Based on this, this paper will review the roles of different cell types in OC differentiation of RA bone metabolism and their research progress to provide new perspectives for the development of multi-targeted combined therapeutic strategies against RA bone metabolism abnormalities.

Bone metabolism is the result of bone remodeling and is mainly regulated by two cell types, OC, which is responsible for bone resorption, and OB, which is responsible for bone formation, and the dynamic balance between the two is important to maintain the normal physiological metabolism and homeostasis of the skeleton. When osteoclastic activity is hyperactivated and osteoblastic function is inhibited, OC activation is increased, causing an imbalanced OC/OB relationship, with the occurrence of abnormal bone meabolism. and the OC/OB relationship is imbalanced, abnormal bone metabolism occurs (6). Both RA and osteoporosis (OP) are closely related diseases of bone metabolism. However, there are significant differences in the activation mechanisms and influence patterns of OC in the two diseases. Them. In OP, the activation of OC is mostly closely related to systemic factors, such as estrogen deficiency and aging, which is manifested as systemic decrease in bone density and bone strength, and the same manifestations occurs in the early period of RA. In RA, the activation of OC is limited to localized joints and interacts with inflammation, forming a complex network of “immunity/inflammation-OC overactivation-bone metabolism imbalance,” which ultimately drives the progressive erosion and destruction of bones and joints in RA patients (6). It has been shown that about 2/5 rheumatoid arthritis patients have bone erosion (7, 8). In RA, the concentration of inflammatory factors, such as TNFα, IL-1, and IL-6, is elevated in the synovium and joints, forming a localized inflammatory microenvironment and activating the activity of OC precursors in the synovium. At the same time, immune cells such as Th17 cells and B cells and synovial fibroblasts in the synovium activate OC by secreting pro-inflammatory TNF-α, IL-17 and other cytokines and signaling molecules such as RANKL, and activated OC releases catalases and acid enzymes, which are the main causes of increased bone resorption leading to bone erosion in RA patients (9). Elevated levels of inflammatory cytokines inhibit bone formation not only by activating OC but also by inhibiting OB activity. Multiple pathologic mechanisms intersect with each other eventually causing joint and bone destruction and joint deformity (10). The current first-line therapeutic drugs for RA include methotrexate (MTX) and glucocorticoids, etc. However, studies have shown that MTX can prevent OB reduction and increased bone resorption. Long-term use of glucocorticoids will inhibit the activity of osteoblasts and simultaneously activate the OC precursors in the bone marrow to promote bone resorption, which affects bone metabolism and causes a decrease in bone density (3). In addition, several studies have found (11, 12) that vitamin D deficiency is negatively correlated with disease activity in RA, and that vitamin D supplementation significantly improves disease activity in RA patients. 1,25-dihydroxyvitamin D3, the active form of vitamin D, can regulate calcium metabolism, reduce parathyroid hormone secretion, maintais bone metabolism homeostasis, and have an immunomodulatory effect that reduces the production of pro-inflammatory cytokines (13). Therefore, for the abnormal bone metabolism in RA, in addition to conventional anti-inflammatory treatment, attention needs to be paid to the regulatory mechanisms of OC to achieve more effective bone protection.

OC is the only multinucleated giant cell with bone resorption function in vivo and plays a crucial role in maintaining bone homeostasis. OB is differentiated from MSCs. It stimulates the differentiation of OC precursors through secreting regulatory factors, such as nuclear factor κB receptor-activating factor ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), meanwhile, inhibits overactivation involved in the regulation of OC differentiation by secreting OPG (RANKL decoy receptor) (14, 15). In physiological state, OC-mediated bone resorption and OB-dominated bone formation maintain a dynamic balance and work together to maintain skeletal metabolic homeostasis. However, under RA pathology, abnormal expression of RANKL and M-CSF occurs, which in turn disrupts the original equilibrium and significantly promotes OC differentiation and activation. In RA patients, the levels of pro-inflammatory cytokines, such as TNF-α and IL-6, are significantly elevated, inducing an increase in the expression of RANKL in peripheral blood mononuclear cells (PBMC) (16), and the high expression of RANKL drives the generation of a large number of highly activated OC, which increases bone resorption, and is the core driver of the imbalance of bone metabolism and bone destruction in RA patients (17). Studies have shown (18) that the accumulation of large amounts of OC in synovial tissues of RA patients, and the interaction between bone metabolic imbalance caused by abnormally differentiated OC and the local inflammatory microenvironment are the main causes of intra-articular bone erosion and localized bone destruction in the joints of RA patients. OC also plays an important role in the regulation of the immune system (19). In the RA pathological environment, OC actively secretes factors such as TNF-α, IL-6, and IL-1 during bone resorption, which affects the activity of immune cells and drives macrophage polarization toward M1 type (20). It has been found that macrophages are circulating precursors of OC, and synovial macrophages can develop into mature OC with luminal absorptive capacity, through which forming a self-perpetuating cycle of “OC-inflammatory factor-M1 macrophage-new OC” (21). The over-activation of OC has an important impact on the RA immune microenvironment. In addition, RA synovial tissue maintains a hypoxic microenvironment due to vascular opacification, which induces stable expression of hypoxia-inducible factor 1α (HIF-1α) and up-regulation of RANKL, and further promotes differentiation of osteoclastic precursor cells into OC (22, 23). Calcium ions (Ca²⁺) released by mature OC can activate RA synovial fibroblasts (RA-FLSs), and activated RA-FLSs can secrete more M-CSF and inflammatory factors, which will further enhance the bone resorption activity of OC, and release more Ca²⁺ by differentiating matured OC. In reverse, the increasing Ca²⁺ will stimulate RA-FLSs to secret more related factors to exacerbate the imbalance of RA bone metabolism and aggravate the condition, Such a vicious circle ultimately leads to the thorough disruption of bone metabolism balance (24) and makes the degree of erosion and destruction of RA patients’ bones and joints more and more serious. The activation and differentiation of OC not only lead to bone resorption, but also degrade the bone matrix through the release of a variety of enzymes such as TRAP, CTSK and MMP9, results in further exacerbation of joint destruction. What’s more, it dynamically interacts with the inflammatory and hypoxic microenvironment of the synovial tissues, which ultimately drives the progressive erosion and destruction of the bones and joints of patients with RA, and weave together the complex network of “immunity/inflammation - over-activation of OC - imbalance of bone metabolism - bone destruction of joints.

OC is the driving and critical cells for bone erosion and destruction in RA. The differentiation of OC in RA can be influenced by different cell types, and immune and non-immune cells form a complex regulatory network by secreting different cytokines and regulating metabolic reprogramming, ultimately leading to over-activation of OC and imbalance of bone resorption (Table 1; Figure 1).

The mechanism of bone metabolism malfunction in RA is a complex pathological process involving multiple immune cells and mesenchymal stromal cells, the core of which lies in the disruption of bone metabolism homeostasis caused by the chronic inflammatory microenvironment triggered by immune system dysregulation. Under normal physiological conditions, the dynamic balance of bone metabolism whose function is strictly regulated, relies on the synergistic action of multiple cells regulating OC differentiation. However, in the pathological environment of RA, multiple pro-inflammatory factors and mediators interact with each other in the microenvironment of inflammation, hypoxia, and immune dysregulation, which significantly promotes the abnormal activation and differentiation of OC, exacerbates bone erosion and the destruction of joint structure, and eventually leads to irreversible bone damage and dysfunction in RA patients.

Among the immune abnormalities in RA, the aberrant interactions between T cells and B cells are particularly critical. The binding of T cells to CD40 on the surface of B cells through surface CD40L not only activates signaling pathways within B cells to promote their proliferation and differentiation, but also further strengthens the cellular immune response through the recognition of B-cell MHC-antigen peptide complex by the T-cell receptor (TCR) (66, 67). B cells present citrullinated antigenic peptides to T cells via MHC-II, activating autoreactive CD4⁺ T cells, especially Th1 and Th17, which directly stimulate OC differentiation. In addition, although B cells secrete OPG to maintain bone metabolic homeostasis (68), their abnormally activated cells secrete RANKL to promote OC formation. Thus, a vicious cycle of “T-B cell contact → B cell activation → autoantibodies + proinflammatory factors → synovial inflammation → bone destruction” is formed. Macrophages in RA synovium show a significant M1/M2 polarization imbalance, with M1-type macrophages predominating and releasing large amounts of pro-inflammatory factors, such as TNF-α, IL-1β, IL-6, etc. These cytokines not only directly stimulate OC precursor cell differentiation, but also activate FLSs and promote their secretion of RANKL and MMPs, which further exacerbate bone resorption and cartilage degradation. What is more, M1-type macrophages maintain a chronic inflammatory state through the NF-κB and MAPK signaling pathways, forming a positive feedback loop that perpetuates the progression of bone destruction. NETs cause joints damage by activating RA-FLSs. By delivering the citrullinated peptide segments that they carry to FLSs, NETs not only activate the antigen-presenting function of FLSs, but also promote autoimmune responses and cartilage degradation (69). FLSs interacts with VECs through adhesion molecules such as ICAM-1/VCAM-1-integrin, which promotes inflammatory cell extravasation and neovascularization to form vascular opacities. This aberrant interaction also leads to dysfunction of VECs, releasing pro-angiogenic factors such as VEGF and ANG-2, exacerbating synovial hypoxia and acidification, and further stimulating OC activation. Meanwhile, the continuous interaction between FLSs and VECs maintains the chronic inflammatory state of RA, which makes the bone erosion around synovial joints much worse (70). As the disease progresses, the sustained inflammatory response will ultimately lead to bone erosion, joint deformity and loss of function. Bone erosion in RA is the result of multiple cellular interactions: in the initiation phase, the interaction is shown as “abnormal T-B cell contact → autoantibody + Th17 activation → synovial inflammation”; and in the amplification phase, it is expressed like “macrophage M1 polarization, FLSs activation, NETs release → TNF-α/IL-6/IL-17 storm→RANKL/OPG imbalance”; while in the Terminal phase, it is manifested as “hypoxic microenvironment + MMPs + OC overactivation→cartilage degradation and bone resorption”.

The abnormal RA bone metabolism is the result of a ternary interaction model of “inflammation/immunity-bone metabolism malfunction-bone erosion and destruction,” which is formed by the interaction of inflammatory immune cell polarization, metabolic reprogramming and bone remodeling signals. However, there still exist several problems in the current research. In the RA-related research, despite the breakthrough progress in exploring the functions of cell types, there are still many key scientific problems in the cell–cell interaction network that need to be solved. At the level of cellular interactions, although it has been confirmed that there is a complex regulatory relationship between various immune cells and mesenchymal stromal cells, the specific molecular mechanisms and signaling pathway networks have not yet formed a systematic knowledge. In addition, cell interactions are dynamically regulated by multi-dimensional factors such as genetic polymorphisms, environmental triggers and immune homeostatic imbalance, and how these factors affect RA disease heterogeneity by remodeling cellular communication networks will be an important direction for future research. An integration of single-cell multi-omics (transcriptome, epigenome) and spatial metabolomic technologies will be required in the future research, so that the spatiotemporal dynamics of immune-mesenchymal cell interactions in RA synovium could be analyzed, and the targeting of specific metabolic pathways could be validated, providing a basis for the development of precision therapies targeting specific cell subpopulations.

In general, RA, as a complex chronic inflammatory autoimmune disease, has a complex regulation at the cellular level at the core of its pathogenesis. RA bone metabolism is closely related to osteoclasts, and different types of effector cells, including T cells, B cells, and so on, have a significant impact on osteoclast differentiation in RA patients. However, the heterogeneity of interactions between different cell types, cytokine networks and signaling pathways makes individualized treatment a great challenge. Further integrate multidisciplinary techniques will be needed in the future studies to facilitate the development of precision medicine and bring more effective treatment options to patients!