{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T04:00:11Z","timestamp":1793073611834,"version":"4.5.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied by local and systemic bone loss. Fc\u03b3Rs, especially Fc\u03b3RIIa (hFc\u03b3RIIa), have been implicated in the pathogenesis of RA. However, the contribution of hFc\u03b3RIIa to bone loss has not been fully elucidated. In the present study, we demonstrated the double-edged sword role of hFc\u03b3RIIa on osteoclast differentiation through investigations involving hFc\u03b3RIIa-transgenic (hFc\u03b3RIIa-Tg) mice. Our findings reveal that hFc\u03b3RIIa-Tg mice, previously shown to exhibit heightened susceptibility to collagen-induced arthritis (CIA), displayed increased osteoporosis during CIA or at advanced ages (40 weeks), accompanied by heightened <jats:italic>in vivo<\/jats:italic> osteoclast differentiation. Notably, bone marrow cells from hFc\u03b3RIIa-Tg mice exhibited enhanced efficiency in differentiating into osteoclasts and bone resorption <jats:italic>in vitro<\/jats:italic> compared to wild-type mice when stimulated with receptor activators of NF-\u03baB ligand (RANKL). Additionally, hFc\u03b3RIIa-Tg mice exhibited augmented sensitivity to RANKL-induced bone loss <jats:italic>in vivo<\/jats:italic>, highlighting the osteoclast-promoting role of hFc\u03b3RIIa. Mechanistically, bone marrow cells from hFc\u03b3RIIa-Tg mice displayed heightened Syk self-activation, leading to mTOR-pS6 pathway activation, thereby promoting RANKL-driven osteoclast differentiation. Intriguingly, while hFc\u03b3RIIa crosslinking hindered RANKL-induced osteoclast differentiation, it activated the kinase cAbl, subsequently triggering STAT5 activation and inhibiting the expression of osteoclast-associated genes. This study provides novel insights into hFc\u03b3RIIa-mediated osteoclast biology, suggesting promising therapeutic targets for managing bone remodeling disorders.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1425670","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T04:57:45Z","timestamp":1724993865000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["hFc\u03b3RIIa: a double-edged sword in osteoclastogenesis and bone balance in transgenic 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