Mitogen Inducible Gene-6 in Joint Health and Osteoarthritis

Osteoarthritis (OA) is the most common type of arthritis or degenerative disease and leads to chronic and functional disability affecting a patient’s quality of life. The etiology of OA is a heterogeneous multifactorial disease, with inflammatory, metabolic, and mechanical causes. Therefore, OA commonly affects a heterogeneous population, ranging widely from the middle-aged and elderly populations, although younger people may be affected as a result of injury or overuse. Moreover, OA is characterized by loss of articular cartilage, changes in subchondral bone, synovium and supporting structures that ultimately affect all the tissues necessary for joint function. Despite an increasing awareness of OA as a medical problem, there is a surprising absence of effective medical treatments beyond pain control and surgery. The progressive understanding of the pathophysiology of OA leads to the perception that the disease is not purely mechanical or aging, and clarification of the signalling pathways and molecular mechanisms is necessary to the clinical application. Our lab has demonstrated the importance of Epidermal Growth Factor Receptor/Mitogen Inducible Gene 6 (EGFR/Mig-6) for joint development. I hypothesized that Mig-6 regulates cartilage homeostasis. We first started investigating the role of Mig-6 in cartilage using cartilage-specific (Col2) overexpression of Mig-6 in a mouse model. Using histopathological assessment, histological and imaging techniques, we concluded that these animals showed significantly greater cartilage breakdown with aging, while younger Mig-6over/over mice resulted in healthy articular cartilage. Moreover, μCT analysis showed small but significant reductions in the size of long bones of Mig-6over/over mice compared to control group (wild type). To further analyze the in vivo animal model, we subsequently assessed Mig-6 in cartilage using skeleton (Prx1)-specific overexpression. I again evaluated the morphology of articular cartilage using histological techniques and long bones of these mice and concluded similar results from the previous study, I found that mice overexpressing Mig-6 displayed significantly cartilage damage. Subsequently, we compared the disease progression between mice with cartilage-specific (Col2) overexpression of Mig-6 and controls after destabilization of medial meniscus surgery (DMM) to induce post-traumatic osteoarthritis (PTOA). Mig-6over/over mice exhibited behavioural changes (vertical activity count) and appeared to show accelerated cartilage breakdown in surgically induced OA. Collectively, these data demonstrate that Mig-6 plays an important mediating role in articular cartilage homeostasis and development of osteoarthritis. Overexpression of this protein compromises the joint’s homeostatic mechanisms, predisposing them to accelerated degeneration