{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:47:59Z","timestamp":1793908079990,"version":"4.8.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>IL-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-\u03baB ligand (RANKL) concentration and osteoclast differentiation were determined. Additionally, a collagen-induced arthritis mouse model was established and treated with IL-34 neutralizing antibody. The arthritis score, paw swelling, histopathological analysis micro-CT analysis were conducted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Upregulated serum IL-34 level in RA patients was correlated with disease severity and bone erosion. IL-34 overexpression facilitated proliferation, migration and invasion and inhibited apoptosis in FLS. Moreover, CM from IL-34-overexpressing FLS promoted macrophage recruitment and M1 polarization. In contrast, IL-34 silencing showed the opposite results. rhIL-34-stimulated FLS-macrophage coculture exhibited higher RANKL production and enhanced osteoclast differentiation. However, RANKL inhibitor denosumab abolished these effects. IL-34 blockade attenuated RA severity, synovial hyperplasia, macrophage M1 polarization, inflammatory infiltration, and bone erosion in CIA mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IL-34 accelerates RA progression by regulating FLS-macrophage crosstalk to amplify bone erosion through RANKL-dependent osteoclastogenesis. We suggest that IL-34 blockade as a promising therapeutic strategy for concurrently alleviating synovial hyperplasia, inflammation, and bone erosion in RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1822793","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T21:39:03Z","timestamp":1781732343000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["IL-34-mediated fibroblast-like synoviocyte-macrophage crosstalk drives bone erosion in rheumatoid arthritis through RANKL-dependent osteoclastogenesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Rheumatology, First Affiliated Hospital of Jinzhou Medical University","place":["Jinzhou, Liaoning, 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