title: RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation.
abstract: RANKL is mainly expressed by synovial fibroblasts and T cells within the joints of rheumatoid arthritis patients. The relative importance of RANKL expression by these cell types for the formation of bone erosions is unclear. We therefore aimed to quantify the contribution of RANKL by each cell type to osteoclast differentiation and bone destruction during inflammatory arthritis.
  
  
  
  RANKL was specifically deleted in T cells (Tnfsf11(flox/Δ) Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11(flox/Δ) Col6a1-Cre) and in collagen II expressing cells including articular chondrocytes (Tnfsf11(flox/Δ) Col2a1-Cre). Erosive disease was induced using the collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA) models. Osteoclasts and cartilage degradation were assessed by histology and bone erosions were assessed by micro-CT.
  
  
  
  The inflammatory joint score during CAIA was equivalent in all mice regardless of cell-targeted deletion of RANKL. Significant increases in osteoclast numbers and bone erosions were observed in both the Tnfsf11(flox/Δ) and the Tnfsf11(flox/Δ) Lck-Cre groups during CAIA; however, the Tnfsf11(flox/Δ) Col6a1-Cre mice showed significant protection against osteoclast formation and bone erosions. Similar results on osteoclast formation and bone erosions were obtained in CIA mice. The deletion of RANKL on any cell type did not prevent articular cartilage loss in either model of arthritis used.
  
  
  
  The expression of RANKL on synovial fibroblasts rather than T cells is predominantly responsible for the formation of osteoclasts and erosions during inflammatory arthritis. Synovial fibroblasts would be the best direct target in RANKL inhibition therapies.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan Explorative Research for Advanced Technology (ERATO) Program, Japan Science and Technology Agency (JST), Takayanagi Osteonetwork Project, Tokyo, Japan.
authors.forename: Lynett
authors.initials: L
authors.lastname: Danks
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Komatsu
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan Explorative Research for Advanced Technology (ERATO) Program, Japan Science and Technology Agency (JST), Takayanagi Osteonetwork Project, Tokyo, Japan.
authors.forename: Matteo M
authors.initials: MM
authors.lastname: Guerrini
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan Explorative Research for Advanced Technology (ERATO) Program, Japan Science and Technology Agency (JST), Takayanagi Osteonetwork Project, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sawa
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Marietta
authors.initials: M
authors.lastname: Armaka
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan Explorative Research for Advanced Technology (ERATO) Program, Japan Science and Technology Agency (JST), Takayanagi Osteonetwork Project, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016723:Bone Remodeling / Q000502:physiology; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D008297:Male; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse
keywords: Cytokines; Inflammation; Rheumatoid Arthritis; Synovitis; T Cells