Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion. Macrophage colony stimulating factor (M-CSF) is abundant in rheumatoid arthritis (RA). However, the role of M-CSF in arthritic bone erosion is not completely understood. Here, we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS, a receptor for M-CSF, leading to the generation of FMS intracellular domain (FICD) fragments. Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses. Moreover, myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model. The FICD formed a complex with DAP5, and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATc1 protein expression. Moreover, targeting the MNK1/2 pathway diminished arthritic bone erosion. These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.

破骨细胞是骨吸收细胞，在稳态骨重塑和病理性骨侵蚀中起着重要作用。巨噬细胞集落刺激因子 (M-CSF) 在类风湿性关节炎 (RA) 中含量丰富。然而，M-CSF 在关节炎骨侵蚀中的作用尚不完全清楚。在这里，我们表明 M-CSF 可以通过触发 c-FMS（M-CSF 的受体）的蛋白水解来促进破骨细胞生成，从而导致 FMS 细胞内结构域 (FICD) 片段的产生。增加的 FICD 片段水平正向调节破骨细胞生成，但对炎症反应没有影响。此外，小鼠骨髓细胞特异性 FICD 表达导致炎症性关节炎模型中破骨细胞介导的骨吸收显着增加。FICD 与 DAP5 形成复合体，FICD/DAP5轴通过激活MNK1/2/EIF4E通路和增强NFATc1蛋白表达促进破骨细胞分化。此外，靶向 MNK1/2 通路可减少关节炎骨侵蚀。这些结果确定了 c-FMS 蛋白水解在破骨细胞生成和关节炎骨侵蚀的发病机制中的新作用。