Role of Meniscus Micromechanics in Joint Function and Osteoarthritis

The meniscus, a crescent-shaped fibrocartilage located between the femur and tibia ends of the knee, is an essential component of knee joint, responsible for stability, load transmission and lubrication. The unique biomechanical function of the meniscus is endowed by its hierarchically structured extracellular matrix (ECM). The knee meniscus has very limited self-healing capabilities, especially in the inner avascular, proteoglycan-rich zone. Currently, the mechanical knowledge of meniscus is mostly limited to the tissue level, so it is unclear how such unique ECM structure across multiple length scales endows the tissue with its specialized mechanical properties. The first part of the dissertation studied the anisotropy and heterogeneity of the micromechanical properties of the meniscus ECM in normal joint function as well as during maturation by using innovative atomic force microscopy (AFM) based nanomechanical tools. The systematic structure-mechanics understanding of the meniscus can serve as benchmark for understanding meniscus biomechanical function, documenting disease progression and designing tissue repair strategies. Injuries in the meniscus often lead to the development of post-traumatic osteoarthritis (PTOA) which is the most prevalent form of osteoarthritis (OA) among the younger population. Among different types of PTOA repair and amelioration, small molecule treatment has been considered as one target since it plays a critical role not only in signaling pathway, but also in extracellular matrix. The second part of the dissertation was to investigate the role of decorin, a major small leucine rich proteoglycan (SLPR), in meniscus dysfunction induced PTOA progression. After destabilization of medial meniscus (DMM) surgery, decorin knockout mice underwent accelerated aggrecan loss and cartilage damage, signifying increased susceptibility to OA. Since decorin and biglycan are two structurally similar SLRPs, the inducible knockout of decorin / biglycan or both has been studied to delineate the roles of decorin and biglycan during OA progression. By using the inducible knockout mice, mice can develop normally before the surgery, thus the decorin's role during OA progression can be isolated from biological development. By deleting decorin or biglycan expression at the time of DMM surgery, decorin appears to play a more dominating role than biglycan, as illustrated by its more severe phenotype in inducible knockout model and elevated expression in wild type cartilage under OA condition. These results underlined decorin for serving as an indispensable constituent to the structural and functional integrity of cartilage ECM, and set a basis for developing decorin-based cartilage regeneration and repair strategies.Ph.D., Biomedical Science -- Drexel University, 201