A9.10 Synovial activation drives anti-inflammatory effects of adipose-derived stem cells after local administration in experimental oa which is reflected by s100a8/a9 levels in the serum

Abstract

Backgound and Objectives Synovitis is evident in a substantial subpopulation of patients with early osteoarthritis (OA) and has been associated with development of pathophysiology. Recently we have shown that adipose-derived stem cells (ASC) inhibit joint destruction after local application to knee joints with experimental OA. In the current study we explored the effect of synovitis on the immunomodulatory capacity of ASCs after local administration in two experimental OA models differing in synovitis. Material and Methods ASCs were isolated from fat surrounding the popliteal lymph nodes. ASCs were injected into knee joints after induction of collagenase-induced OA (CiOA) characterised by synovitis and surgically induced DMM model in which synovitis is scant. Synovial activation, chondrogenesis in ligaments and osteophytes were measured using histology. Cytokines in synovial washouts and serum were determined using Luminex. Active TGFβ was measured using the CAGAluc assay. Results ASCs injected into knee joints at different time-points after induction of DMM (day 7, day 14 or day 7 and day 14) had no effect on development of ligament damage or osteophyte formation. In contrast, ASC treatment of collagenase-induced OA knee joints, rapidly inhibited synovitis and ligament damage when administered at day 7 after induction. Washouts of synovium taken at different time points after injection of ASCs (6 hrs, day 2, day 14 and day 42) showed significantly decreased levels of IL-1β and S100A8/A9 already at 48 hrs after ASC treatment. No effect was found on levels of active TGFβ. Serum levels of S100A8/A9 were significantly decreased (85% lower) at day 14 whereas IL-1 levels were not detectable at that time-point. Next, we explored the effect in CiOA in a condition with less synovial inflammation. Synovial thickness at day 42 was 62% lower when compared to the former study. Injection of the same dose of ASCs at day 7 after induction of CiOA, only marginally inhibited synovial thickening when measured at day 42. Serum levels of S100A8/A9 were low at day 14 (around 50 ng/ml compared to 800 ng/ml in the first experiment) and were not altered by the ASC treatment. Chondrogenesis in collateral and cruciate ligaments but also osteophyte formation at the bone margins was also not diminished. Conclusion Our study indicates that synovial activation rapidly drives anti-inflammatory effects of ASCs after local administration in murine OA knee joints with synovitis protecting against development of ligament damage and osteophyte formation.