Background The main pathological feature of osteoarthritis (OA) is degradation of the articular cartilage. Other important hallmarks include subclinical inflammation of the synovium and ectopic formation of new bone and cartilage at the ligaments or joint margins, termed osteophytes. Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (1) (OA).
Objectives In the current study we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and if S100A8/A9 predicts osteophyte progression in early human OA.
Methods OA was elicited in S100A9 -/- and wild-type C57Bl/6 mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN expression was measured on histology. Chondrogenesis was induced in murine mesenchymal stem cells (MSCs) in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA patients of the CHECK cohort study and osteophyte size measured at baseline and after 2 and 5 years.
Results S100A8 and S100A9 protein levels in the synovial lining and serum coincide with osteophyte development in collagenase-induced OA (CIOA), in which synovial activation is high. Osteophyte size was drastically reduced in S100A9 -/- mice on day 21 and 42 of CIOA, in the medial collateral ligaments (58% and 93% reduction) and at medial femur and tibia (62% and 67% reduction). In contrast, osteophyte size was not reduced in S100A9 -/- mice during destabilized medial meniscus OA, in which synovial activation is scant. One explanation for the reduced osteophyte size in S100A9-/- mice may be a direct effect of S100-proteins on chondrogenesis. During in vitro chondrogenesis using murine MSCs, S100A8 caused a marked increase in MMP-3 mRNA and VDIPEN expression (as measure for MMP activity) as well as a strongly altered morphology, indicating increased remodeling allowing for larger osteophytes. Interestingly, early symptomatic OA patients of the CHECK study with osteophyte progression after two and five years had significantly elevated S100A8/A9 plasma levels at baseline, while CRP, COMP and ESR were not higher.
Conclusions S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte formation in early human OA.
van Lent PL, Blom AB, Schelbergen RF, Sloetjes A, Lafeber FP, Lems WF, et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis and rheumatism. 2012 May; 64(5):1466-1476
Disclosure of Interest None declared
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