33 34 Background: Osteoarthritis (OA) is the most common form of arthritis and characterized by 35 degeneration of articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a 36 negative regulator of the Epidermal Growth Factor Receptor (EGFR). Cartilage-specific Mig-6 37 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of articular cartilage 38 and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network 39 in cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of 40 Mig-6 in this study. 41 Methods: Utilizing knee joints from cartilage-specific Mig-6 overexpressing (Mig-6over/over ) mice 42 (at multiple time points), we evaluated the articular cartilage using histology, 43 immunohistochemical staining and semi-quantitative OARSI scoring at multiple ages. MicroCT 44 analysis was employed to examine skeletal morphometry, body composition, and bone mineral 45 density. 46 Results: Our data show that cartilage-specific Mig-6 overexpression did not cause any major 47 developmental abnormalities in articular cartilage, although Mig-6 over/over mice have slightly 48 shorter long bones compared to the control group. Moreover, there was no significant difference 49 in bone mineral density and body composition in any of the groups. However, our results indicate 50 that Mig-6 over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. 51 Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-52 6 over/over mice decreased relative to controls. Immunostaining for MMP13 staining is increased in 53 areas of cartilage degeneration in Mig-6 over/over mice. Moreover, staining for phospho-EGFR (Tyr-54 1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6 over/over mice. 55 Conclusion: Overexpression of Mig-6 in articular cartilage causes no major developmental 56 phenotype; however these mice develop earlier OA during aging. These data demonstrate that 57