Temporomandibular joint (TMJ) disorders, or TMD, refers to a group of clinical disorders that affect the TMJ and its associated structures. TMJ Osteoarthritis (TMJ OA) is a major subtype of TMDs, which affects 10-16% of the population exhibiting TMD and is secondary to disc displacement, trauma, developmental abnormalities and overload on the joint. Degeneration of mandibular condyle cartilage is a major hallmark of TMJ OA and degradation of its extracellular matrix (ECM) has been identified as a key feature of TMJ OA. Therefore, it is critical to understand the changes in the ECM and identify the molecular mechanisms governing TMJ OA progression, which can provide a foundation for developing early detection and repair strategies.

In the first part of the dissertation, we define the biomechanical and structural properties of murine TMJ articular disc and condyle cartilage in the normal joint (wild-type, WT), and delineate the roles of type V collagen (collagen V) in 3-month-old collagen V heterozygous (Col5a1^+/-) mice using atomic force microscopy (AFM)-based nanomechanical tools and electron microscopy. By evaluating 3-month-old WT mice, we reported that the condyle fibrocartilage exhibits significantly higher modulus compared to all five regions of both superior and inferior disc. We further quantified the regional specific micromoduli on both sides of the disc. This knowledge will serve as a benchmark for understanding TMJ biomechanical function and documenting disease pathogenesis in various murine models. Indeed, we reported compromised biomechanical properties and significantly thicker collagen I fibrils on the fibrocartilage layer of the Col5a1^+/- condyle. Collagen V is a regulatory fibril-forming collagen, that is involved in the collagen I fibril assembly. In addition to its expected role in regulating the fibrocartilage layer, this dissertation uncovered a new role of collagen V in secondary hyaline cartilage of TMJ condyle, where we identified similar phenotype in this collagen II-dominated region. Collagen V is clinically important as its mutation causes classical Ehlers-Danlos Syndrome (cEDS), a connective tissue disorder. Thus, this study will provide further insights into higher prevalence of TMJ OA in patients suffering from cEDS.

The second part of the dissertation investigates susceptibility of Col5a1^+/- mice to TMJ OA. To demarcate the roles of collagen V in TMJ OA, we applied the unilateral anterior crossbite prosthesis (UAC) procedure to induce aberrant TMJ loading to Col5a1^+/- mice. Three weeks after UAC, Col5a1^+/- mice exhibited reduction in the modulus of the condyle fibrocartilage layer and an increase in aggrecan staining in the underlying hyaline cartilage, in addition to significant changes to cell arrangement in comparison to WT. These signs together led to higher Mankin OA scores, signifying increased susceptibility to condyle degradation. In the final section, we further investigate the age-specific impact of collagen V deletion in post-natal joint development using collagen V inducible knockout mice (Col5a1^iKO). By deleting the collagen V expression at 1 week and 1 month of age, we revealed different developmental roles for collagen V in both articular disc and mandibular condyle. These results highlight the importance of collagen V in serving as an indispensable constituent to the structural and functional integrity of TMJ condyle ECM, and provides a basis for developing collagen V-based TMJ condyle regeneration and repair strategies to ameliorate TMJ OA.