Osteoarthritis, also known as OA, is a leading cause of disability in United States, which affects over 30 million adults and leads to more than $128 billion financial burden. One of the important factors that can increase the risk of OA is traumatic joint injury, e.g., meniscus or ligament tears in the knee joint, commonly affecting younger population including athletes and military service. Traumatic events often cause physical injury of cartilage and render the chondrocytes under OA- inducing stimulations, such as inflammation, bleeding, and altered loading patterns. These stimulations significantly accelerate the OA development, however there is no existing treatment that can effectively prevent disease initiation. Thus, a significant unmet clinical need exists for preventing early initiation of OA after joint injuries. This dissertation highlights a potential biologically-driven solution using a statin therapy.

Statins are an FDA-approved class of drugs prescribed to over 40 million U.S. people to control the cholesterol levels. In this thesis, using the patient database at Christiana Health Care System, I investigated the impact of statin use on the clinically defined OA occurrence in the Delaware population. It’s shown that the use of statin was associated with significantly lower occurrence of OA and other common musculoskeletal disorders, e.g. joint pain and low back pain. Furtheremore, integrating experimental and bioinformatics data, my thesis revealed that the joint-favoring effects of statins were through inhibiting a fundamental metablic pathway called mevaloante pathways and its downstream Rho GTPase signaling in chondoryctes. Rho GTPase proteins play essential roles in regulating aberrant phenotypic shift and catabolic activities of chondrocytes under OA-inducing stimulations. Statins can directly inhibit the activation of Rho GTPase proteins and prevent the chondrocytes from entering a degradative state, therefore protecting the cartilage from degeneration.

Taken together, this thesis involves interdisplinary approaches and contributes to the discovery of potential treatments of OA. The mevalonate pathway and its downstream Rho GTPases in chondrocytes could be a new target for cartilage protection. Repurposing of statins might represent a new pharmaceutical solution for OA prevention. More importantly, the finding that statin use is associated with significant OA reduction in Delaware population could increase the prescription adherence of current statin users, especially those at high risk of OA development due to joint injury histories.