Impaired signaling through the Fms‐like tyrosine kinase 3 receptor increases osteoclast formation and bone damage in arthritis

Flt3L−/− is a negative regulator of OC differentiation by affecting expression of IRF8, and regulating the balance between Treg and Th17. Osteoclasts are bone‐resorbing cells that accumulate in the joints of patients with rheumatoid arthritis causing severe bone damage. Fms‐like tyrosine kinase 3 ligand is enriched in the synovial fluid of patients with rheumatoid arthritis, and local exposure to Fms‐like tyrosine kinase 3 ligand aggravates arthritis in mice. Because Fms‐like tyrosine kinase 3 ligand has been suggested to facilitate osteoclast differentiation, we asked whether Fms‐like tyrosine kinase 3 ligand affects bone remodeling in arthritis. The effect of Fms‐like tyrosine kinase 3 signaling on osteoclast development was studied by immunohistochemistry in methylated bovine serum albumin–induced arthritis using mice that lack the gene for Flt3l (Flt3L−/−) and by an in vitro assay. Bone and joint changes were studied morphologically and by microcomputer tomography. We found that Flt3L−/− mice had increased accumulations of osteoclasts in the periarticular area of the arthritic joint. This triggered bone destruction and trabecular bone loss. The increased number of osteoclasts in Flt3L−/− mice may be a consequence of insufficient expression of interferon regulatory factor 8. Treatment of Flt3L−/− mice with Fms‐like tyrosine kinase 3 ligand increased expression of interferon regulatory factor 8, reduced the number of osteoclasts in arthritic mice, and promoted trabecular bone formation. Finally, the reduced number of regulatory T cells in the bone marrow of Flt3L−/− mice could further contribute to the increased osteoclastogenesis by reducing the ratio of regulatory T cells to T helper 17 cells. This study shows that Fms‐like tyrosine kinase 3 ligand may serve as a negative regulator of osteoclast development by promoting transcription of interferon regulatory factor 8 and sustaining a balance between protective regulatory T cells and pathogenic T helper 17 cells in the pathogenesis of arthritis.