Bone Research (Oct 2021)

Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion

  • Se Hwan Mun,
  • Seyeon Bae,
  • Steven Zeng,
  • Brian Oh,
  • Carmen Chai,
  • Matthew Jundong Kim,
  • Haemin Kim,
  • George Kalliolias,
  • Chitra Lekha Dahia,
  • Younseo Oh,
  • Tae-Hwan Kim,
  • Jong Dae Ji,
  • Kyung-Hyun Park-Min

DOI
https://doi.org/10.1038/s41413-021-00162-0
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 11

Abstract

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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.