The Role of Osteoclast Differentiation in Bone Destruction of Rheumatoid Arthritis

Osteoclasts, as the central effector cells of bone resorption, exhibit aberrant differentiation and activation that serve as key drivers of bone destruction in rheumatoid arthritis (RA). This article systematically reviews the multi-level regulatory network governing osteoclast differentiation in RA, with a particular emphasis on the dysregulation of the RANKL/RANK/OPG signaling axis, the synergistic effects of pro-inflammatory cytokines (TNF-α, IL-6, IL-17), metabolic reprogramming (a shift from glycolysis to oxidative phosphorylation), and enhanced reactive oxygen species (ROS) signaling. Studies indicate that within the inflammatory synovial microenvironment of RA, RANKL derived from synovial fibroblasts, together with inflammatory cytokines, promotes the efficient differentiation of a novel pathological osteoclast precursor subset—arthritis-associated osteoclastogenic macrophages (AtoMs). This process is primarily mediated through the STAT3/NFATc1 signaling axis and leads to the formation of localized quiescent bone erosion foci. Furthermore, damage-associated molecular patterns (DAMPs) released by necrotic bone cells—such as SAP-130 and β-GlcCer—exacerbate pathological osteoclastogenesis via activation of the SYK/NFATc1 pathway through their receptor Mincle. This article also discusses emerging therapeutic strategies, including SMART-Cas9 gene editing targeting RhoA in AtoMs and inhibition of osteoclast-specific super-enhancers (SEs). Additionally, it highlights the potential of targeting metabolic pathways and overexpressing the immune checkpoint protein TIPE2—which concurrently modulates cytokine storms and osteoclast differentiation—to prevent bone destruction. These findings provide a critical theoretical foundation for developing novel and precise therapeutic interventions to inhibit bone erosion in RA.