Objective: To study the active involvement of S100A8 and A9 in joint inflammation and cartilage destruction during antigen-induced arthritis (AIA).
Methods: Joint inflammation and cartilage destruction was measured with 99mTc uptake and histology. The role of S100A8/A9 was investigated by inducing AIA in S100A9-/- mice, which lacks also S100A8 at protein level, or after intra-articular injection of rS100A8 in mouse kneejoints. Cartilage destruction was measured using immunolocalisation of the neoepitope VDIPEN or NITEGE. mRNA levels of MMPs and cytokines were measured using RT-PCR.
Results: Immunization of S100A9-/- mice with the antigen mBSA induced normal cellular and humoral responses, not different from WT controls. However, joint swelling measured at day 3 and 7 after AIA induction was significantly lower (36 and 70% respectively). Histologically, at day 7 AIA, cellular mass was much lower (63- 80%) and proteoglycan depletion from cartilage layers was significantly reduced (between 50-95%). Cartilage destruction mediated by MMPs was absent in S100A9-/- mice but clearly present in controls. MMP3, 9 and 13 mRNA levels were significantly lowered in arthritic synovia of S100A9-/-. In vitro stimulation of macrophages by the heterodimer S100A8/A9 or S100A8 elevated mRNA levels of MMP3, 9 and in particular MMP13. Intra-articular injection of S100A8 caused prominent joint inflammation and depletion of proteoglycans at day 1. Significant upregulation of mRNA levels of S100A8/A9, cytokines (IL-1), MMPs (MMP-3, MMP-13 and ADAMTS4) was found in the synovium and correlated with strong upregulation of NITEGE neoepitopes within the cartilage layers.
Conclusions: S100A8/A9 regulate joint inflammation and cartilage destruction during antigen-induced arthritis.
- cartilage destruction
- experimental arthritis
- synovial lining macrophages