RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation

Author:

Danks Lynett,Komatsu Noriko,Guerrini Matteo M,Sawa Shinichiro,Armaka Marietta,Kollias George,Nakashima Tomoki,Takayanagi Hiroshi

Abstract

ObjectiveRANKL 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.MethodsRANKL was specifically deleted in T cells (Tnfsf11flox/ΔLck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11flox/ΔCol6a1-Cre) and in collagen II expressing cells including articular chondrocytes (Tnfsf11flox/ΔCol2a1-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.ResultsThe 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 Tnfsf11flox/Δ and the Tnfsf11flox/ΔLck-Cre groups during CAIA; however, the Tnfsf11flox/ΔCol6a1-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.ConclusionsThe 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.

Publisher

BMJ

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology

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