Osteoarthritis (OA) is a progressively debilitating condition involving joint degeneration that causes substantial joint stiffness and pain, decreased mobility, and increased health care costs. Despite approximately 27 million Americans being afflicted with this disease, there are no medical treatments that significantly alter its progressin. Currently, an individual suffering from OA will only be proscribed pain management medication, physical therapy and lifestyle modification, and in end---stage disease a joint replacement surgery will be advised. Injections of cytokines and proteoglycans have shown some promise in clinical and pre---clinical trials, yet due to the rapid degradation and turnover of these compounds, repeated injections are necessary to obtain any long---lasting results, potentially leading to an increase in adverse events. Major obstacles to the development of new treatments for OA have include both the difficulty of identifying quantifiable endpoints for progression in animal models, and the complex cell autonomous and non---cell autonomous components of the pathophysiology of the joint. To overcome these obstacles, our lab developed a novel imaging technique combining staining, phase--- contrast optics, and microCT analysis of the joint, which allows the robust quantification of murine cartilage volume, surface area, and osteophyte formation. To address the issue of the complex etiology of OA development, our lab has identified secreted molecules as potential therapeutic targets - Proteoglycan 4 (PRG4) and the anti---inflammatory Interleukin 1 Receptor antagonist (IL1Ra). PRG4 is a major component of the cartilage extracellular matrix and mediates mechanical stress by providing lubrication. Inflammation has also been attributed to disease progression, and IL1Ra has been proven to function as an anti---inflammatory through the inhibition of Interleukin 1 (IL1). Both published work and preliminary data from our lab and others shows that individually each provides some protection from OA progression. We hypothesize that combinatorial therapy with both PRG4 and IL1Ra will provide increased protection from OA development and progression through addressing cartilage matrix loss and inflammation.
We aim to test this by comparing the effects of combinatorial therapy to mono---therapy in a post---traumatic model and in an age---related model of OA development, as the balance of individual factors contributing to disease is different in each. Prior studies have also shown that PRG4 potentially mediates cartilage protection through inhibition of the hypoxic response via upregulation of the inhibitory hypoxia inducible factor 3a (Hif3a); therefore in the third aim of this project we will investigate this futher through the generation and characterization of a cartilage---specific Hif3a transgenic mouse, and determine whether it is also protected from OA development and progression. This research is important for establishing new treatment options and therapeutic targets for patients with osteoarthritis.
This project serves to investigate a combinatorial gene therapy for the treatment of Osteoarthritis (OA), which addresses multiple aspects of OA progression. Pathophysiology of OA is complex and its causes are not well understood; however, inflammation and cartilage matrix loss are critical known contributors, and are directly targeted by our vector through the expression of Proteoglycan 4 (PRG4) and Interleukin 1 receptor antagonist (IL1Ra). Through this research we hope to develop new targets and therapeutic options for OA, a disease that affects millions of Americans and has few treatments that are able to markedly affect progression.
