Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Frank Beier

Abstract

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases in the world. Our laboratory has shown that epidermal growth factor receptor (EGFR) signalling is involved in the process of cartilage degeneration in OA. Regulation of EGFR signalling by mitogen-inducible gene 6 (Mig-6) and dual specificity phosphatase 1 (DUSP-1) allows for signal modulation, and mouse models have linked these proteins to joint pathologies. Failure to control EGFR signalling may be involved in OA progression leading to my overarching hypothesis: regulation of EGFR signalling is essential for maintenance of joint health.

I initially tested the role of Mig-6 in cartilage health using cartilage-specific deletion of Mig-6 in a mouse model. Using various histological and imaging techniques, we demonstrated that these animals show increased anabolic activity in articular cartilage, as well as the formation of chondro-osseous nodules in their knee joints within the first 3 months. These mice did not develop severe OA as I predicted, however, there were early signs of developing articular cartilage pathology.

To assess the role of Mig-6 in elderly cartilage, we employed the same mouse model but aged these animals to 21 months, near the end of their life span. These KO animals exhibited similar knee phenotypes, however, no abnormal growths were observed in the ankle and elbow joints which showed enhanced cartilage thickness. Only minor signs of OA were noted. Using an inducible system to delete Mig-6 from cartilage of 3 week old mice, we found limited evidence of increased anabolic activity at 12 weeks. These studies demonstrate that Mig-6 may be playing an important role during development and that loss of Mig-6 may positively impact cartilage health.

Finally, I examined the knee joints of whole body Dusp1 null mice at 21 months of age for signs of OA. Both Dusp1 null and control mice showed similar signs of OA, indicating that DUSP-1 mediated regulation of signalling downstream of EGFR is not essential to prevent spontaneous OA progression.

Taken together, these data demonstrate that EGFR signalling regulated by both Mig-6 and DUSP-1 is important in joint homeostasis, and has revealed a potential target in Mig-6 for future cartilage regenerative treatments.

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