FRI0526 IL37 AMELIORATES EXPERIMENTAL MURINE OSTEOARTHRITIS

Abstract

Background Osteoarthritis (OA) is the world’s most common degenerative joint disorder and leads to pain and disability. Currently, no disease-modifying drugs are available, resulting in a large unmet clinical need. Recently, we have shown that the anti-inflammatory cytokine IL37 lowers pro-inflammatory cytokine production, MMP3 activity and sulfated glycosaminoglycan loss from ex vivo cultured chondrocytes and human cartilage explants. In this study, we further explored the ability of IL37 to ameliorate OA pathology by studying its effects both in vitro on synovial fibroblasts and in vivo in collagenase-induced OA Objectives To establish if IL37 can ameliorate experimental OA pathology Methods Primary synovial fibroblasts were obtained from synovial biopsies of 10 patients undergoing total joint replacement surgery. IL37 was overexpressed in these cells using an adenovirus and subsequently cells were challenged with IL1β or OA-synovium conditioned medium. Collagenase-induced OA (CiOA) was induced by injecting 10 weeks old female C57BL/6J with a single intra-articular injection of 3 units of collagenase type VII. Four days after collagenase injection, Ad-IL37 or Ad-Luc (= control) was intra-articular injected in the right knee joint of mice. Two weeks later this injection was repeated. Mice were sacrificed on day 7, 28 and 42 after collagenase-injection. Synovial thickening, cartilage damage and osteophyte formation were measured histologically. IL37, MMP3 and VDIPEN expression were investigated by immunohistochemistry. Results In primary synovial fibroblasts, IL37 overexpression significantly reduced IL1β- and OAS-CM-induced expression of MMP1, MMP3, IL1B and IL6 by more than 50%. In naive knee joints, IL-37 overexpression did not induce synovial thickening, cartilage damage or osteophyte formation and no overt immune response was detected after 28 days. Strikingly, in CiOA, at day 7, IL37 overexpression significantly reduced synovial thickening and the presence of the metalloproteinase-generated aggrecan-degradation neoepitope VDIPEN in cartilage. At day 28 of CiOA, cartilage degradation was significantly reduced by IL37 treatment at the lateral and medial femur by respectively 46% and 41%, and osteophyte size at the medial femur was reduced by 70%. At day 42 of CiOA, IL37 overexpression could no longer be detected. Osteophyte size formation at the medial femur was still significantly reduced by 46% at this time point, but only a trend (p = 0.06) towards reduced cartilage damage was observed on both femur and tibia. Conclusion Our results show that IL37 inhibits the production of catabolic mediators in synovial fibroblasts, similar to our previously obtained results in cartilage. Furthermore, IL37 clearly lowered synovial thickening and ameliorated cartilage damage and osteophyte formation in murine experimental OA. These results indicate that IL37 acts on multiple tissues and OA-related processes, which supports IL37 as a potential therapeutic agent for OA Disclosure of Interests None declared