PROJECT SUMMARY/ABSTRACT The goal of this proposal is to understand the role of ADAMTS5 during temporomandibular joint (TMJ) development. TMJ disorders afflict over 20 million Americans, yet they are an understudied area. Specifically, TMJ osteoarthritis (TMJOA) is of particular concern because it disrupts extracellular matrix (ECM) homeostasis leading to cartilage degradation and subchondral bone erosion. Upregulated A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTS)-5 cleavage of aggrecan, the most abundant TMJ proteoglycan, has been considered a hallmark of TMJOA. However, the majority of research on ADAMTS5- ECM turnover has focused on hyaline cartilage, not fibrocartilage, which comprises the TMJ. Additionally, our preliminary data demonstrates that ADAMTS5 proteolytic activity is required for establishment of the fibrocartilage cell zones in the young adult TMJ. Therefore, this fellowship proposal tests the hypothesis that ADAMTS5-mediated aggrecan cleavage is vital for the development of the mandibular condyle in the TMJ. To study this hypothesis, three specific aims are proposed. Specific Aim 1 will investigate the consequence of ADAMTS5 deficiency during embryonic and early postnatal fibrocartilage cell layer development. Specific Aim 2 will elucidate the mechanistic requirement of ADAMTS5-mediated aggrecan cleavage for chondrocyte hypertrophy and subchondral bone formation. Finally, Specific Aim 3 will determine the role of mechanical load on the developing mandibular condyle in combination with ADAMTS5 deficiency. This proposal is calling into question the existing theory that ADAMTS activity is primarily destructive to cartilage. Our preliminary data indicate a critical role for ADAMTS5-mediated aggrecan cleavage in chondrocyte maturation and mandibular condylar development. In addition these experiments investigate the requirement for coupling of extracellular matrix turnover with mechanical loading to promote normal TMJ development and homeostasis. Results from this study will provide a more thorough understanding of fibrocartilage biology for the development of regenerative techniques in the treatment of TMJ disorders.