Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis.

OBJECTIVE: Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA. METHODS: OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years. RESULTS: Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline. CONCLUSIONS: S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.

Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis.

OBJECTIVES: Alarmins S100A8/A9 regulate pathology in experimental osteoarthritis (OA). Paquinimod is an immunomodulatory compound preventing S100A9 binding to TLR-4. We investigated the effect of paquinimod on experimental OA and human OA synovium. MATERIALS AND METHODS: Two OA mouse models differing in level of synovial activation were treated prophylactic with paquinimod. Synovial thickening, osteophyte size and cartilage damage were measured histologically, using an arbitrary score, adapted Pritzker OARSI score or imaging software, respectively. Human OA synovia were stimulated with S100A9, with or without paquinimod. RESULTS: Paquinimod treatment of collagenase-induced OA (CIOA) resulted in significantly reduced synovial thickening (57%), osteophyte size at the medial femur (66%) and cruciate ligaments (67%) and cartilage damage at the medial tibia (47%) and femur (75%; n=7, untreated n=6). In contrast, paquinimod did not reduce osteophyte size and reduced cartilage damage at one location only in destabilised medial meniscus, an OA model with considerably lower synovial activation compared with CIOA. In human OA synovium, paquinimod blocked proinflammatory (interleukin (IL)-6, IL-8, tumour necrosis factor-α) and catabolic (matrix metalloproteinases 1 and 3) factors induced by S100A9 (n=5). CONCLUSIONS: Prophylactic treatment of paquinimod reduces synovial activation, osteophyte formation and cartilage damage in experimental OA with high synovial activation (CIOA) and ameliorates pathological effects of S100A9 in OA synovium ex vivo.

Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels.

OBJECTIVE: Synovitis is evident in a substantial subpopulation of patients with osteoarthritis (OA) and is associated with development of pathophysiology. Recently we have shown that adipose-derived stem cells (ASC) inhibit joint destruction in collagenase-induced experimental OA (CIOA). In the current study we explored the role of synovitis and alarmins S100A8/A9 in the immunomodulatory capacity of ASCs in experimental OA. METHOD: CIOA, characterized by synovitis, and surgical DMM (destabilization of medial meniscus) OA were treated locally with ASCs. Synovial activation, cartilage damage and osteophyte size were measured on histological sections. Cytokines in synovial washouts and serum were determined using Luminex or enzyme-linked immunosorbent assay (S100A8/A9), mRNA levels with reverse-transcriptase (RT)-qPCR. RESULTS: Local administration of ASCs at various time-points (days 7 or 14) after DMM induction had no effect on OA pathology. At day 7 of CIOA, already 6 h after ASC injection mRNA expression of pro-inflammatory mediators S100A8/A9, interleukin-1beta (IL-1ß) and KC was down-regulated in the synovium. IL-1ß protein, although low, was down-regulated by ASC-treatment of CIOA. S100A8/A9 protein levels were very high at 6 and 48 h and were decreased by ASC-treatment. The protective action of ASC treatment in CIOA was only found when high synovial inflammation was present at the time of deposition which was reflected by high serum S100A8/A9 levels. Finally, successful treatment resulted in significantly lower levels of serum S100A8/A9. CONCLUSION: Our study indicates that synovial activation rapidly drives anti-inflammatory and protective effects of intra-articularly deposited ASCs in experimental OA which is reflected by decreased S100A8/A9 levels.