Overexpression of Mig-6 in Limb Mesenchyme Leads to Accelerated Osteoarthritis in Mice

Abstract

36Background: Mitogen-inducible gene 6 (Mig-6) is a tumour suppressor gene that is also 37 associated with the development of osteoarthritis (OA)-like disorder. Recent evidence from our 38 lab and others showed that cartilage-specific Mig-6 knockout (KO) mice develop chondro-39 osseous nodules, along with increased articular cartilage thickness and enhanced EGFR signaling 40 in the articular cartilage. Here, we evaluate the phenotype of mice with skeletal-specific 41 overexpression of Mig-6. 42 43 Methods: Synovial joint tissues of the knee were assessed in 12 and 36 weeks-old skeleton-44 specific Mig-6 overexpressing (Mig-6 over/over ) and control animals using histological stains, 45 immunohistochemistry, semi-quantitative OARSI scoring, and microCT for skeletal 46 morphometry. Measurement of articular cartilage and subchondral bone thickness were also 47 performed using histomorphometry. 48 49 Results: Our results show only subtle developmental effects of Mig-6 overexpression. However, 50 male Mig-6 over/over mice show accelerated cartilage degeneration at 36 weeks of age, in both 51 medial and lateral compartments of the knee. Immunohistochemistry for SOX9 and PRG4 52showed decreased staining in Mig-6 over/over mice relative to controls, providing potential 53 molecular mechanisms for the observed effects. 54