title: Impaired signaling through the Fms-like tyrosine kinase 3 receptor increases osteoclast formation and bone damage in arthritis.
abstract: 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.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden mattias.svensson@rheuma.gu.se.
authors.forename: Mattias N D
authors.initials: MN
authors.lastname: Svensson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ing-Marie
authors.initials: IM
authors.lastname: Jonsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications*; D001862:Bone Resorption / Q000209:etiology*; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D050835:Interferon Regulatory Factors / Q000032:analysis / Q000502:physiology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis; D015398:Signal Transduction / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D051941:fms-Like Tyrosine Kinase 3; D000099185:Interferon Regulatory Factor-8; C084881:flt3 ligand protein
keywords: Flt3L; IRF8