WISP1/CCN4 aggravates cartilage degeneration in experimental osteoarthritis

Objective: Increased Wisp1 expression was previously reported in experimental and human osteoarthritis (OA). Moreover, adenoviral overexpression of Wisp1 in naïve mouse knee joints resulted in early OA-like cartilage lesions. Here, we determined how the matricellular protein WISP1 is involved in the pathology that occurs in the complex osteoarthritic environment with aging and experimental OA in wild type (WT) and Wisp1^−/− mice. Methods: WT and Wisp1^−/− mice were aged or experimental OA was induced with intraarticular collagenase injection, destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT). Joint pathology was assessed using histology and microCT. Protease expression was evaluated with qRT-PCR and activity was determined by immunohistochemical staining of the aggrecan neoepitope NITEGE. Protease expression in human end-stage OA synovial tissue was determined with qRT-PCR after stimulation with WISP1. Results: With aging, spontaneous cartilage degeneration in Wisp1^−/− was not decreased compared to their WT controls. However, we observed significantly decreased cartilage degeneration in Wisp1^−/− mice after induction of three independent experimental OA models. While the degree of osteophyte formation was comparable between WT and Wisp1^−/− mice, increased cortical thickness and reduced trabecular spacing was observed in Wisp1^−/− mice. In addition, we observed decreased MMP3/9 and ADAMTS4/5 expression in Wisp1^−/− mice, which was accompanied by decreased levels of NITEGE. In line with this, stimulation of human OA synovium with WISP1 increased the expression of various proteases. Conclusions: WISP1 plays an aggravating role in the development of post-traumatic experimental OA.