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

Ann Rheum Dis. 2016 Jun;75(6):1187-95. doi: 10.1136/annrheumdis-2014-207137. Epub 2015 May 29.

Abstract

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) 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.

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 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.

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.

Keywords: Cytokines; Inflammation; Rheumatoid Arthritis; Synovitis; T Cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • Bone Remodeling / physiology
  • Bone Resorption / etiology
  • Bone Resorption / metabolism*
  • Bone Resorption / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology
  • Cell Differentiation
  • Chondrocytes / metabolism
  • Fibroblasts / metabolism*
  • Gene Deletion
  • Male
  • Mice, Inbred C57BL
  • Osteoclasts / pathology
  • RANK Ligand / genetics
  • RANK Ligand / metabolism*
  • Synovial Membrane / metabolism*

Substances

  • RANK Ligand
  • Tnfsf11 protein, mouse