hFcγRIIa: a double-edged sword in osteoclastogenesis and bone balance in transgenic mice

Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied by local and systemic bone loss. Fc gamma Rs, especially Fc gamma RIIa (hFc gamma RIIa), have been implicated in the pathogenesis of RA. However, the contribution of hFc gamma RIIa to bone loss has not been fully elucidated. In the present study, we demonstrated the double-edged sword role of hFc gamma RIIa on osteoclast differentiation through investigations involving hFc gamma RIIa-transgenic (hFc gamma RIIa-Tg) mice. Our findings reveal that hFc gamma RIIa-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 in vivo osteoclast differentiation. Notably, bone marrow cells from hFc gamma RIIa-Tg mice exhibited enhanced efficiency in differentiating into osteoclasts and bone resorption in vitro compared to wild-type mice when stimulated with receptor activators of NF-kappa B ligand (RANKL). Additionally, hFc gamma RIIa-Tg mice exhibited augmented sensitivity to RANKL-induced bone loss in vivo, highlighting the osteoclast-promoting role of hFc gamma RIIa. Mechanistically, bone marrow cells from hFc gamma RIIa-Tg mice displayed heightened Syk self-activation, leading to mTOR-pS6 pathway activation, thereby promoting RANKL-driven osteoclast differentiation. Intriguingly, while hFc gamma RIIa 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 gamma RIIa-mediated osteoclast biology, suggesting promising therapeutic targets for managing bone remodeling disorders.