Chondrocyte specific expression of CCN2 does not modify osteoarthritis development in mice

Purpose: CCN2 is a matricellular protein which has been shown to be heavily involved in several complex biological processes including angiogenesis, fibrosis, and chondrogenesis. CCN2 is known to be expressed in both healthy and osteoarthritic cartilage, and involved in the production of the major cartilage matrix proteins; aggrecan and collagen type II. CCN2 null mice have been reported to exhibit a range of skeletal dysmorphisms, highlighting the importance of CCN2 in regulating matrix formation and turnover. The aim of this study was to determine the function of CCN2 in chondrocytes postnatally, in models of trauma-induced osteoarthritis (OA). Methods: Three double transgenic mouse models were generated; two inducible CCN2 knockout (KO) lines and one inducible CCN2 overexpressing (O/E) line. Both CCN2 KO lines contained Aggrecan CreERT2 enhancers which enabled the deletion of CCN2 from different populations of chondrocytes, whilst the O/E line contained an UbcCCN2-IRES-LacZ transgene enabling CCN2 O/E in all chondrocytes. CCN2 deletion and overexpression was induced following tamoxifen treatment in males aged 8 weeks. OA was induced either through surgical injury (transection of the medial meniscus and medial menisco-tibial ligament), or non-invasively by applying a controlled loading regimen to the tibio-femoral joint at 10 weeks of age. Knee joints were harvested and fixed, scanned with μCT, and processed for histology. Sections were stained with Toluidine Blue and scored for articular cartilage degeneration using the OARSI grading system. Results: In the surgical model of OA, cartilage degeneration was most severe on the medial side of the joint, however no significant differences were observed between lesion severity in wildtype (WT) and KO at any of the time-points analysed (2, 4, and, 8 weeks post-surgery). In the non-invasive model of OA lesion severity was most severe on the lateral femur in both the KO and O/E lines. As with the surgical model, no differences in lesion severity were observed between WT / KO and WT / O/E when analysed 6 weeks post-loading. μCT analysis of trabecular bone BV/TV and joint space in both models showed no effect of CCN2 KO and O/E between WT and experimental animals. Conclusions: CCN2 did not appear to play a protective role in the development of OA irrespective of whether the damage was induced surgically or non-invasively. The progression and severity of OA in both models, at all time-points, suggests the expression of CCN2 specifically in chondrocytes is not enough to protect articular cartilage from the degeneration associated with trauma-induced OA.