Background Synovitis is evident in a substantial subpopulation of patients with early osteoarthritis (OA). Recently we have shown that adipose derived stem cells (ASC) inhibit synovitis and joint destruction after local application to knee joints with experimental OA.
Objectives To explore whether the efficacy of the anti-inflammatory effect of locally administered ASCs into experimentally induced osteoarthritic joints is stimulated by an inflammatory milieu.
Methods ASCs were isolated from fat surrounding the popliteal lymph nodes. Murine OA was induced by either dissection of the anterior medial menisco-tibial ligament (DMM) or by injection of collagenase into murine knee joints (CIOA). CIOA clearly develops synovitis in contrast to DMM in which synovitis is scant. ASCs were injected into OA knee joints and OA phenotype was measured within 6 weeks after induction. Total knee joints were processed for histology. Synovitis and joint destruction was measured using an arbitrary score from 0-3. Synovial washouts were measured for S100A8/A9 and IL-1 using Luminex.
Results The effect of local ASC treatment was first investigated in DMM in which synovitis is scant. ASCs (20X103) injected in knee joints at days 7 or 14 after induction of DMM, showed no effect on development of cartilage destruction or osteophyte formation at day 42. To investigate whether ASC need an inflammatory milieu to become protective they were locally injected in the CIOA model in which synovitis is severe. A day 7 intra-articular injection of ASC showed a clear protective effect on joint destruction at day 42. Injection of GFP-labeled ASC displayed a tight interaction with synovial lining macrophages. To study the effect on the inflammatory status within the joint, washouts of synovium were taken at various time-points (6 hrs, 48 hrs, day 14 and day 42) after ASC treatment. Protein levels of pro-inflammatory mediators IL-1 and S100A8/A9 were significantly decreased already 48 hrs after ASC injection (22% and 57% respectively) and rapidly declined thereafter. Histology showed that synovial thickness was significantly inhibited at day 14 (9%) and day 42 (35%) when compared to control treated OA joints and protected joint destruction (osteophyte formation inhibition 67%). Serum levels of S100A8/A9 which are strongly raised during CIOA, were inhibited by 85% at day 14 after ASC treatment. Next, we explored the anti-inflammatory effect of ASCs in a milder CIOA exhibiting less synovial inflammation. Synovial thickening at day 42 was 62% lower when compared to the former study. Injection of ASCs at day 7 after OA induction, only marginally inhibited synovial thickening and formation of osteophytes when measured at day 42 suggesting that severe synovial inflammation is needed for a clear anti-inflammatory effect of ASC. Serum levels of S100A8/A9 were low at day 14 (around 50 ng/ml compared to 800 ng/ml in CIOA with high synovitis) and not significantly altered by ASC treatment.
Conclusions Our study indicates that the anti-inflammatory effects of ASCs after local administration in murine OA knee joints is stimulated by a severe inflammatory milieu. S100A8/A9 serum levels may predict the protective outcome of ASC treatment.
Disclosure of Interest None declared
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