Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Beier, Frank.

Abstract

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.

Summary for Lay Audience

Osteoarthritis (OA) is a slowly progressive degenerative joint disease characterized by loss of articular cartilage. Our current understanding of the pathophysiology of OA suggests that the disease is not purely caused by mechanical factors or aging, and clarification of the biochemical and inflammatory pathways involved is necessary to develop new therapies. The economic and social impact of OA due to direct medical costs, loss of work time and quality of life are considerable.

Currently, there are no treatment options available to slow, stop or reverse the course of OA, and the etiology of the disease is poorly understood. Thus, additional work to reveal the underlying pathobiology is required if treatment options are to be developed. Therefore, our laboratory has focused on elucidating the molecular mechanism relevant to OA using animal models, cell and organ culture, and biochemical techniques.

We have identified that the epidermal growth factor receptor (EGFR) signaling pathway is involved in regulating the health of cartilage and other joint structures. In particular, we are interested in a gene called mitogen-inducible gene 6 (Mig-6) that regulates EGFR signaling, and loss of this protein has been shown to lead to severe joint dysfunction in mice. Using genetically modified mice lacking Mig-6 in critical joint tissues our laboratory showed that deletion of Mig-6 resulted in thicker articular cartilage with extra, abnormal cartilage surrounding the knee. My project focuses on whether overexpression of Mig-6 is enough to cause OA.

Indeed, my work shows that higher levels of Mig-6 in cartilage and other joint tissues leads to faster and more severe OA both during aging and after injury. Altogether, these studies may indicate Mig-6 and EGFR as potential therapeutic targets in the treatment of osteoarthritis and similar diseases.

Available for download on Saturday, March 05, 2022

Share

COinS