RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation
L Danks, N Komatsu, MM Guerrini, S Sawa… - Annals of the …, 2016 - ard.bmj.com
Annals of the rheumatic diseases, 2016•ard.bmj.com
Objective 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. Methods RANKL was specifically deleted in T cells (Tnfsf11
flox/Δ Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11 flox/Δ …
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. Methods RANKL was specifically deleted in T cells (Tnfsf11
flox/Δ Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11 flox/Δ …
Objective
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.
Methods
RANKL was specifically deleted in T cells (Tnfsf11flox/Δ Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11flox/Δ Col6a1-Cre) and in collagen II expressing cells including articular chondrocytes (Tnfsf11flox/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.
Results
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 Tnfsf11flox/Δ and the Tnfsf11flox/Δ Lck-Cre groups during CAIA; however, the Tnfsf11flox/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.
Conclusions
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.
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