IL-34-mediated fibroblast-like synoviocyte-macrophage crosstalk drives bone erosion in rheumatoid arthritis through RANKL-dependent osteoclastogenesis

BackgroundThe crosstalk between fibroblast-like synoviocytes (FLS) and macrophages forms a self-reinforcing vicious feedback loop in the rheumatoid arthritis (RA) immune microenvironment. Upregulated interleukin-34 (IL-34) levels in RA patients correlate with RA severity.

This study investigated the roles and mechanisms of IL-34-mediated FLS-macrophage crosstalk in osteoclastogenesis-associated bone erosion in RA.MethodsIL-34 expression in the RA serum and synovial samples and its correlation with disease severity and bone erosion were assessed. Primary FLS were transfected with IL-34 overexpression plasmids or short hairpin RNA (shRNA) targeting IL-34, and cell proliferation, migration, invasion and apoptosis were examined.

Then, conditioned medium (CM) from these FLS were incubated with THP-1-differeniated macrophages to evaluate macrophage migration and polarization. FLS, M1 macrophages, and their cocultures were respectively treated with recombinant human IL-34 (rhIL-34), and these CM were incubated with peripheral blood mononuclear cells (PBMCs).

Receptor activator of NF-κB ligand (RANKL) concentration and osteoclast differentiation were determined. Additionally, a collagen-induced arthritis mouse model was established and treated with IL-34 neutralizing antibody.