Cellular heterogeneity and niche regulation in TMJ

PROJECT SUMMARY Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative joint disease of the jaw and a major driver of temporomandibular disorders (TMDs) that affects approximately 11 million individuals in the United States alone. TMDs are commonly characterized by severe pain and functional defects that lead to TMJ dysfunction and negatively affect the quality-of-life in patients. However, the developmental and pathophysiological mechanisms in TMJ development and disease are poorly understood, thus creating significant barriers to identifying novel non-invasive treatments for TMDs. Here, we aim to examine the cell lineage heterogeneity and molecular mechanisms that contribute to TMJ development and assess how TMJ cell subpopulations are dysregulated in disease. We hypothesize that the fibrous surface layers of the mandibular condyle are composed of unique progenitor cell populations that regulate TMJ development and may contribute to TMJ-OA pathophysiology. Further, we will examine how alterations in the structural organization of the progenitor niche can impact cell lineage plasticity. In Aim 1, we will use single-cell transcriptomic analysis, lineage tracing, and TMJ-OA preclinical modeling to define unique cell subpopulations in the TMJ and their role in TMJ-OA pathogenesis. In Aim 2, we will determine how impaired organization of the fibrous superficial layers of the mandibular condyle alters TMJ progenitor cell differentiation using single-cell multi-omics approaches and investigate the underlying molecular mechanisms that cause TMJ dysfunction.