Augmenting MNK1/2 Activation by c-FMS Proteolysis Promotes Osteoclastogenesis and Arthritic Bone Erosion

초록

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder. Bone erosion is one of the key clinical features of RA and is closely linked to impaired mobility of patients with RA. Osteoclasts are bone-resorbing cells and play an essential role in homeo-static bone remodeling and arthritic bone erosion. However, the underlying mechanisms of arthritic bone erosion by osteoclasts have not been fully determined. In addition to inflam-matory cytokines such as tumor necrosis factor-alpha (TNF-α), macrophage colony-stimu-lating factor (M-CSF) and its receptor c-FMS have also been implicated in the pathogenesis of RA and arthritic bone erosion. In patients with RA, the level of M-CSF increases in the serum and synovial fluid, and inhibition of c-FMS activation attenuates the progression of joint inflammation and bone erosion in animal models of arthritis. Despite the importance of M-CSF in the differentiation of myeloid cells, very little is known about the molecular mechanism underlying the role of M-CSF/c-FMS in arthritic bone erosion. In this study, we identified that M-CSF can promote osteoclasts by triggering proteolysis of c-FMS, a recep-tor for M-CSF, leading to the generation of FMS IntraCellular Domain (FICD) fragments. Increased levels of FICDs positively regulated osteoclastogenesis while having no effect on inflammatory responses. To model the high expression of FICD in vivo, we generated myeloid cell-specific conditional FICD knock-in (FICDtgM) mice. Both FICDtgM male and female mice exhibited decreased bone mass compared to control mice. Moreover, myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model. FICD formed a complex with DAP5, and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathways and enhancing NFATc1 protein expression. Accordingly, targeting MNK1/2 path-ways diminished arthritic bone erosion. Our study identified a novel role of c-FMS prote-olysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion and provided a strong basis for developing a new therapeutic target for pathological bone resorption in RA.