Osteoarthritis (OA) is the most common degenerative joint disease and is expected to affect 67 million Americans by 2030. Little is known about the mechanisms that drive OA progression, which is hallmarked by articular cartilage damage, inflammation, synovitis, and bone sclerosis. Our laboratory has, however, shown that Transforming Growth Factor B Receptor Type II (TBRII) is not only a marker for joint progenitor cells, but also plays a critical role in joint development, homeostasis, and OA progression. Because OA progresses over the course of decades, longitudinal population studies are slow, costly, and difficult to organize. Animal imaging studies can provide crucial insight into OA progression, but they are scarce for two major reasons. First, OA joints degrade in multiple tissues, but standard imaging tools only highlight one tissue type. Second, the accepted OA scoring systems are based on histology, but histological sections are few in number, two- dimensional, and vary anatomically from sample to sample. Also, histological analyses cannot be translated into useful diagnostic tools for human OA. I propose that it is possible to overcome these challenges with the proper use of next-generation imaging systems. I have obtained promising preliminary data in which Micro-Computed Tomography, Magnetic Resonance Imaging, and Optical Imaging modalities have been adapted to identify OA progression in mice. These data imply the feasibility of obtaining quantitative multi- tissue information about OA progression from the same animal. Further, by generating TBRII-GFP:B-Actin- Luciferase double reporter mice, I have designed a means to isolate and track transplanted TBRII-expressing progenitor cells. I propose to use these innovative tools to evaluate OA progression and the effect of TBRII+ cell transplant in OA mice. Namely, this proposal seeks to characterize the spontaneous OA in TBRII knockout (KO) mice and the post-traumatic OA in both TBRII-KO and control mice. The central hypothesis of this proposal is that TBRII-KO induces spontaneous OA and that subsequent TBRII+ cell transplant delays OA progression. In order to test this hypothesis, I will use the novel imaging platform to achieve the following specific aims: 1) to characterize the effect of TBRII-KO on OA progression and 2) to characterize the effect of TBRII+ cell transplant on OA progression. I hypothesize that TBRII-KO mice will develop spontaneous OA and will have accelerated OA progression in response to trauma. Additionally, I propose that TBRII+ cell transplant will delay the progression of both spontaneous and post-traumatic OA.
Public Health Relevance Statement Osteoarthritis (OA) is a painful, often debilitating disease that that is expected to affect 67 million people in the United States alone by 2030. It is critical that we develop better diagnostic tools for OA and improve our understanding of the biological mechanisms that drive OA. By using new imaging techniques to better characterize OA and how biomarker signaling affects OA, this study provides a means to 1) develop new OA diagnostic tools and 2) identify biological targets for OA therapy.
