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.

破骨细胞（Osteoclasts）作为骨吸收的核心效应细胞，其异常分化与活化是类风湿关节炎（RA）骨破坏的关键驱动因素。本文系统综述了类风湿关节炎中调控破骨细胞分化的多层级调控网络，重点聚焦于RANKL/RANK/OPG信号轴、促炎细胞因子（TNF-α、IL-6、IL-17）的协同效应、代谢重编程（从糖酵解向氧化磷酸化的转变）以及活性氧（ROS）信号通路的增强激活。研究表明，在类风湿关节炎炎性滑膜微环境中，滑膜成纤维细胞来源的RANKL与炎性细胞因子共同作用，可高效诱导新型病理性破骨细胞前体细胞亚群——关节炎相关破骨细胞生成性巨噬细胞（AtoMs）的分化。该过程主要通过STAT3/NFATc1信号轴介导，并最终形成局部静止性骨侵蚀病灶。此外，坏死骨细胞释放的损伤相关分子模式（DAMPs，如SAP-130与β-GlcCer）可通过其受体Mincle激活SYK/NFATc1通路，进而加重病理性破骨细胞生成。本文还讨论了新兴治疗策略，包括靶向AtoMs中RhoA的SMART-Cas9基因编辑技术，以及抑制破骨细胞特异性超级增强子（SEs）。同时，本文强调了靶向代谢通路以及过表达免疫检查点蛋白TIPE2的潜力——该蛋白可同时调控细胞因子风暴与破骨细胞分化，从而预防骨破坏。上述研究结果为开发抑制类风湿关节炎骨侵蚀的新型精准治疗手段提供了重要理论基础。