Abstract
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.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder[1]
To further confirm the cellular localization of c-FMS and we compared c-FMS expression between freshly isolated RA synovial CD14+ cells, macrophage colony-stimulating factor (M-CSF)-cultured CD14+ cells from healthy donors, and OA synovial CD14+ cells, we found higher levels of small fragments in RA synovial CD14+ cells, while the levels of FMS intracellular domain (FICD) fragments, we performed immunocytochemistry using an antibody against the C-terminal region of c-FMS in human macrophages, and signals were detected by fluorescence analysis and confocal microscopy
We demonstrated that c-FMS proteolysis was critically involved in the osteoclastogenic responses of macrophages to RANKL and cooperated with the conventional M-CSF/c-FMS signaling pathways. c-FMS is processed into smaller intracellular fragments (FICD fragments) in macrophages by engaging c-FMS-mediated signaling pathways
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder[1]. Bone erosion is one of the key clinical features of RA and is closely linked to impaired mobility in patients with RA2.the underlying mechanisms of arthritic bone erosion by osteoclasts have not been fully determined[3]. We found that inhibiting calpain suppressed increase in FICD fragments in RA synovial CD14+ cells correlated the generation of the FICD in a dose-dependent manner with the shedding of c-FMS, we measured the level of soluble (Supplementary Fig. 4a, b). Blocking c-FMS proteolysis suppresses RANKL-induced osteoclast formation and activity Given that FICD levels were increased in RA synovial CD14+ cells and that the administration of a calpain inhibitor suppressed both inflammation and bone erosion, we hypothesized that c-FMS proteolysis plays an important role in the functions of macrophages, including inflammatory responses and osteoclastogenesis.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
