Genetic correlations in recombinant inbred mouse strains suggest that cartilage repair is positively correlated with protection from osteoarthritis

Abstract

Purpose: The etiology of osteoarthritis (OA) is unknown, however, there appears to be a significant contribution from genetics. We have identified recombinant inbred strains of mice derived from LG/J (large) and SM/J (small) that vary significantly in their susceptibility to post-traumatic OA due to their genetic composition. While in the past, it was considered that articular cartilage could not undergo repair, we have demonstrated that a number of mouse strains, considered “healer” mice, are able to repair articular cartilage. Here we report cartilage repair phenotypes in the same strains of mice in which OA susceptibility was analyzed. We demonstrate that protection from OA is positively correlated with the ability to repair cartilage. These results suggest a shift in the risk paradigm for OA from degeneration to regeneration. Methods: All procedures were approved by the Institutional Animal Care and Use Committee. We used 12 recombinant inbred (RI) strains of mice generated from LG/J by SM/J intercross to test three phenotypes: ear wound healing, articular cartilage repair, and post-traumatic OA. (1) A 2 mm hole was created in the external ears using a biopsy punch (n = 263) at 6 weeks of age and healing outcome was measured at 30-day post-punch. (2) An acute full-thickness articular cartilage injury was introduced in the trochlear groove of 8-week-old mice (n = 126) through microsurgery and healing outcomes were measured at 16 weeks after surgery. (3) OA was induced in 10-week-old mice (n = 53) by destabilization of medial meniscus (DMM). Maximum OARSI score (representing the highest score within all sectioned levels of the knee), summed OARSI score (representing whole joint changes) and synovitis score (representing synovial cell proliferation) were measured 8 weeks post-DMM. Genetic correlations between various traits were calculated as Pearson correlation coefficients of strain means using GraphPad Prism. Results: We found a significant positive correlation between ear wound healing and knee articular cartilage regeneration (r = 0.74, P = 0.006) (Fig. 1A). We observed a strong linear correlation between cartilage regeneration and protection from OA based on summed OARSI (r = 0.49, P = 0.106) as well as maximum OARSI scores (r = 0.50, P = 0.097) (Fig. 1B). Summed and maximum OARSI scores were also significantly associated with each other (r = 0.92, P < 0.0001) (Fig. 1C). While synovitis was not significantly correlated with knee cartilage healing, it showed highly significant positive correlation with maximum OARSI score (r = 0.63, P = 0.028) and summed OARSI score (r = 0.70, P = 0.011) (Fig. 1D). Despite strong significant correlation between ear wound healing and knee cartilage regeneration, there was a weak correlation between ear wound healing and OA. Conclusions: Our study allows, for the first time, the measurement of genetic correlations of regeneration phenotypes with the degeneration phenotypes that are characteristics of PTOA. These results demonstrate a linear relationship between the resistance to OA after DMM surgery in mouse strains of different genotypes in recombinant inbred strains of a “healer” mouse, LG/J and a “non-healer” mouse, SM/J and the ability to heal an articular cartilage defect in the same mouse strains. While cartilage degeneration and regeneration were the phenotypes of primary interest in these studies, we also assessed synovitis in the OA study and thus could correlate synovitis with OA. The correlation between synovitis and OA ranged from 0.63-0.70, which is consistent with reports of patients with OA. Consequently, we have confidence that our correlation of OA with cartilage repair of 0.5 will be reflective of human cartilage degeneration and repair. We predict that the human population will also demonstrate this genetic variability in cartilage repair for which there is already some data derived from the ability to differentiate cartilage from stem cells. Thus, in the future the ability to repair cartilage may be a powerful indicator of the future susceptibility to OA after injury. Lastly, gene variants involved in cartilage repair may be informative as potential treatments for OA.