2017 Theses Doctoral

Development of Biofidelic Culture Models of Osteoarthritis

Silverstein, Amy M.

Osteoarthritis (OA) is a debilitating degenerative joint disease affecting 27 million Americans over the age of 25. Whereas OA is a disease of the entire joint organ, the contribution of the synovium, a specialized lining that envelops the knee joint, to cartilage degeneration and disease progression has been underappreciated. Synovial inflammation often precedes the development of cartilage damage and is observed in early and late stage OA. The onset of synovitis is driven by both elevated concentrations of pro-inflammatory cytokines and tissue debris in the joint space. Accordingly, surgeons have observed cartilaginous debris embedded within the synovium of OA patients presenting with severe synovial hyperplasia. It has been hypothesized that the fibrotic shortening of the synovial capsule results in OA pain and joint stiffness and contributes to further joint destruction through the release of degradative enzymes. Current strategies to treat synovial inflammation and joint pain, such as intra-articular injections and synovectomy, have had limited and variable success.
To this end, cell and tissue engineering culture models provide a versatile platform to study the tissues and cells involved in OA. Our lab has typically employed mechanical overload or cytokine insult of chondrocytes and cartilage explants to study cartilage degradation. Similarly, to isolate the role of synovium in OA, synovial explants or fibroblast-like synoviocytes (FLS) can be exposed to chemical or physical OA stimuli. Although often overlooked as an instigator of OA, cartilage wear particles have been reported to induce synovial inflammation and OA-like joint changes in various animal models. As opposed to non-biologic (metal or plastic) wear particles, small (sub-10um) cartilage wear particles are comprised of extracellular matrix constituents that are degradable and may interact with cells beyond phagocytosis. Using cells derived from the pathologic joint provides the opportunity to study inherent changes to OA cells (both FLS and chondrocytes) within their own de novo extracellular matrix. The work presented in this dissertation aims to combine knowledge from basic science and pre-clinical culture models of OA to develop a clinically relevant disease model using cells derived from clinical samples.