Defining TMJ cartilage progenitors and their regulatory niche for TMJ regeneration

PROJECT SUMMARY The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, respiration, and speech. The TMJ is comprised of a network of muscles, ligaments, and a fibrocartilaginous disc and condyle. TMJ osteoarthritis (OA) causes cartilage loss and pain. TMJ OA poses a major clinical problem, but there are no regenerative therapies. Understanding stem/progenitor cells is critical knowledge in organ tissue regeneration. We previously defined TMJ Lgr5-expressing cells as secretory niche cells critical for supporting TMJ cartilage progenitor cells in a canonical Wnt inhibitory niche. We also defined two secreted Wnt inhibitors, SOST and DKK3, as critical parts of the TMJ cartilage progenitor cell niche. We showed that therapeutic intra- articular injections of SOST ameliorate TMJ OA in a preclinical, mini-pig post-traumatic TMJ OA animal model. However, the identity of the TMJ cartilage progenitor cells regulated by Lgr5+ secretory niche cells and therapeutically targeted by cWnt inhibition is unknown. This R01 renewal proposal builds logically on our previously funded R01. We will investigate candidate TMJ cartilage progenitor cells and their regulatory niche critical for TMJ development, homeostasis, and regeneration. This proposal will: 1) establish the TMJ condyle as a sophisticated model for studying cartilage progenitor cells; 2) leverage basic science to design TMJ OA drugs. These foundational studies are critical for the advent of novel minimally invasive TMJ regenerative therapies.