Abstract Temporomandibular Joint (TMJ) degeneration is a painful and debilitating disease of the synovial joint, affecting over 20 million people in the United States. Obesity, advancing age and mechanical loading are greatest risk factor for many diseases including TMJ degeneration. TMJ degeneration significantly impair the quality of life by causing acute and chronic pain, thus making this disease a global health issue and a financial burden of epidemic proportion. The incidence of the TMJ degeneration is expected to rise substantially as the prevalence of obesity has risen dramatically over the last two-decades. As there is no effective treatment for the TMJ degeneration in an obese and aged individual, there is an unmet clinical need for an effective approach to treat TMJ degeneration. The current proposal seeks to address this unmet clinical challenge using a highly innovative approach of targeting p21 high cells both genetically and therapeutically for the treatment of TMJ degeneration. Our overarching hypothesis is that p21 high cells plays a central role in obesity, age-related and mechanical loading induced TMJ degeneration and targeted elimination of the p21 high cells may alleviate TMJ degeneration. To test this hypothesis, we will define: (1) the role of p21 high cells in osteochondral tissue in obesity and aging induced TMJ degeneration. Using a novel inducible p21-cre ERT2 X td-Tomato mice we will examine the effects of p21 high cells on the homeostasis of the osteochondral tissues of the TMJ in obesity and aging. (2) the pathophysiological mechanism by which p21high cells causes TMJ degeneration. Using the novel mice model (p21-cre ERT2 X td-Tomato X Rela flox/flox), we will examine the effect NF-κB pathway on the senescent cells in TMJ degeneration. 3) To define the role of p21high cells in traumatic TMJ injury and repair. p21-cre ERT2 X td-Tomato mice will be subjected to traumatic injury to TMJ and we will genetically clear the p21 high cells after traumatic injury to see whether we can alleviate TMJ-OA or repair the damaged cartilage. A combination of mechanical, immunohistochemical, molecular biology and histomorphometric techniques coupled with novel genetic mice models will be used to study the proposed specific aims. The proposed project has the immense potential to reveal new regulatory pathways that controls homeostasis of the osteochondral tissues of the TMJ in an obese and aged individual and to open new insight on understanding the disease mechanism and developing therapeutic interventions.