GSE135821
Human Fc?RIIa mediates osteoclastogenesis through a novel noncanonical pathway independent of RANKL and inflammatory cytokines
Under physiological conditions, osteoclasts (OCs) are generated from monocytic osteoprecursors under the stimulation of RANKL and M-CSF, requiring co-stimulatory signals from Fc receptor common ? chain (FcR?) or DNAX-activated protein 12. It has been proposed that immune complexes (ICs) directly potentiate RANKL-mediated osteoclastogenesis by triggering Fc?R-coupled Fc? receptors (Fc?Rs), thereby linking IC accumulation and pathological osteolysis under various disease conditions. However, whether ICs possess pro-osteoclastogenic potential independent of RANKL is unknown. Here we demonstrate that IgG ICs alone can drive the differentiation of human blood monocytes into nonclassical OCs (NOCs) phenotypically and functionally distinguishable from RANKL-induced classical OCs (COCs). This novel noncanonical osteoclastogenesis pathway is triggered by full crosslinking of human Fc?RIIa (hFc?RIIa), or co-ligation of hFc?RIIa and TLR4, and signals through the Src family kinase-STAT5 axis without inducing the expression of NFATc1, a master transcription factor for the previously described osteoclastogenesis pathways. Surprisingly, IgG ICs strongly overrule the generation of COCs driven by RANKL in vitro. More importantly, TRAP+ OCs found in the inflammatory joint tissues of hFc?RIIa-transgenic mice with collagen-induced arthritis bear the NFATc1- phenotype. Our results unmask the “double faces” of IgG ICs in health and disease, and suggest a novel and important pathway for ICs contributing to pathological bone erosion in inflammatory arthritis. Overall design: Monocytes were pre-incubated either with cell culture medium (Medium), LFIC (10µg/ml) or cIgG (10 µg/ml) for 24 hrs.After wash-out, cells were harvested and processed into RNA extraction.