Osteoarthritis is the leading cause of disability among adults in the United States. Traumatic damage to joints, such as meniscal or ligament tears, can induce cartilage degeneration and lead to post-traumatic osteoarthritis (PTOA). Treatments of PTOA are currently similar to those for idiopathic OA. When small cartilage lesions are diagnosed, microfracture surgery often serves as the first line option for repair. However, clinical practice and animal studies have yielded variable and unpredictable healing results after microfracture surgery. In the first half of this thesis, a novel in vitro cartilage-bone explant co-culture system was developed which can simulate the microfracture procedure and post-surgery rehabilitation protocol. This in vitro platform avoids the high financial cost and complexities of in vivo systems, and also enables the longitudinal measurement of the biomechanical and biochemical properties of the newly repaired tissue. Using this system, we found that the availability of TGF-β3 to the bone marrow clot can significantly improve the growth of new cartilage at the lesion site. Moreover, a two-week delayed mechanical stimulation on the cartilage-bone explant generated better outcome than immediate loading after microfracture procedure. This finding implies that a delayed weight bearing on the knee joint after microfracture surgery may improve the long-term outcome.

Few preventive treatments exist for PTOA, although osteoarthritis could often be predicted after joint injuries. It has been found that bisphosphonates (BP), an FDA- approved drug to treat bone loss, could suppress the development of osteoarthritis after various joint injuries in animal studies. The second half of this thesis aims to test a novel hypothesis that the chondro-protective function of BP is related to its direct effect on the chondrocytes. Using in vitro culture system, we found that BP can promote the beneficial effects of mechanical stimulation on cartilage explants without the presence of bone. The expression of anabolic genes in chondrocytes was promoted, while the catabolic genes downregulated. This regulation of metabolic activities of chondrocytes by BP is related to the spontaneous intracellular calcium signaling, the fundamental second messenger for cells. Moreover, the effects of BP on chondrocytes are dependent on the inhibition of mevalonate pathway. Therefore, we also investigate the effects of statins, another family of drug targeting at mevalonate pathway, on the long-term culture of cartilage explants. Statins showed a biphasic effects on the chondrocytes. In short term, stains promoted the expression of anabolic genes in chondrocytes. After long term culture, in contrast, statins reduced the mechanical integrity of cartilage. Therefore, the FDA-approved drugs that inhibit the mevalonate pathway have the potential to prevent or delay the PTOA progression. This study sheds new light on the search for new classes of drugs to inhibit trauma- induced OA.