Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Dr. Frank Beier

Abstract

Background: Researchers demonstrated that inhibition of epidermal growth factor receptor (EGFR) and/or its downstream signal transducer, C-C motif chemokine receptor-2 (CCR2) blocked development of post-traumatic Osteoarthritis (PTOA) in rat model if applied from the time of injury. However, it is unclear how effective these drugs are if treatment is initiated after injury, a situation more translatable to the human condition.

Methods: Osteoarthritis (OA) was induced surgically in 4 groups. Treatment was initiated 4-weeks post-surgery where groups were given 50% DMSO solution(vehicle), AG1478(EGFR-blocker), RS504393(CCR2-blocker), and EGFR+CCR2 combinational inhibitor. Rats were sacrificed 7 and 10weeks after surgery. OA was examined histologically by staining the samples with Safranin-O-fast green and hematoxylin & eosin stain for assessing cartilage and synovial damage respectively.

Results: There are no significant differences seen in treated Osteoarthritis Research Society International (OARSI) and synovitis scores vs vehicle group in both timeline rats.

Conclusion: Thus, our results did not support our hypothesis and the described protective effects of these compounds require application at or immediately after injury.

Keywords: Epidermal Growth Factor Receptor, CCR2, CCL2, post-traumatic Osteoarthritis

Summary for Lay Audience

Osteoarthritis is a joint disorder that affects millions of people and is a leading cause of disability in Canada and around the globe. It is accompanied by severe pain in the affected joints such as hip, knee, and hands. Current treatment is limited to the suppression of symptoms or joint replacement surgery as there is no other treatment available to reverse the damage or prevent the further progression of disease. Scientists are making constant efforts to find out what actually is causing damage to the joint. Appleton et.al in 2015 have found out the inhibition of Epidermal Growth Factor Receptor (EGFR) and Chemokine receptor 2 (CCR2), to be beneficial for preventing further damage if treatment is given right after injury. We tested if the same treatment was given 1 month after causing injury to see if that would work for the circumstances that are more comparable to humans. We have given EGFR, CCR2 and combination of these inhibitors separately to rats and compared it with control groups. On comparison, we did not witness any protection against osteoarthritis. Hence, we concluded that inhibition of EGFR, CCR2, or both starting at 4 weeks after surgery does not protect from progression of post-injury OA, in contrast to administration from the time of injury.

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