Osteoarthritis is a debilitating disease that affects 27 million Americans. Major risk factors for osteoarthritis include mechanical injury and obesity. Prolonged exposure to mechanical overload in the knee joint, either by injury, malalignment, or obesity, is associated with early onset of osteoarthritis. Recent evidence demonstrates that adipose tissue is a metabolically active and produces systemic biofactors known as adipokines. Elevated levels of adipokines, correlated with obesity, are associated with numerous diseases including cardiovascular disease, hypertension, insulin resistance, rheumatoid arthritis, and osteoarthritis. Interestingly, obesity is a significant risk factor for hand osteoarthritis, suggesting a biologic link between obesity and osteoarthritis that is perhaps mediated through adipokines. While many studies investigating in vitro osteoarthritic degradation have focused on cartilage tissue, the menisci have received relatively little attention despite their important functional roles in joint stability and load transfer in the knee. Imaging studies have revealed that meniscal lesions are seen in 70% of early osteoarthritis patients and meniscal damage may precede that of articular cartilage, suggesting that the menisci may be more susceptible to degeneration and could be an early event in osteoarthritis development.
The purpose of the research described in this thesis was to explore the relative susceptibility of cartilage and meniscal tissue degradation to in vitro mechanical overload and adipokine exposure using an immature bovine tissue explant model. To explore the injury response, explants of cartilage and meniscal tissues were compressed at various strain rates to create a spectrum of peak injury forces and cultured for up to nine days post-injury. Despite no visible damage or measureable degradation of meniscal tissue, cell metabolism decreased and cell lysis increased with peak injury force in both cartilage and meniscal tissues. Thus, sub-failure injury can induce biologic damage that may not be readily detected, particularly for menisci. To investigate whether adipose tissue can biochemically induce changes in cartilage and meniscal tissues, explants of cartilage and meniscal tissue were each co-cultured with infrapatellar fat pad or cultured in isolation for two weeks. Interestingly, fat co-culture increased proteoglycan production and release in both cartilage and meniscus. To characterize matrix synthesis and catabolism in a defined culture environment, four adipokines were selected: leptin, visfatin, adiponectin, and resistin. Leptin, visfatin, and resistin all stimulated proteoglycan release while inhibiting proteoglycan incorporation in meniscal explants, but only resistin appeared to affect cartilage at the doses used. Additionally, resistin and fat co-culture stimulated release of newly synthesized proteoglycans from meniscus but not from cartilage.
Overall, these results indicate that, while mechanically robust, meniscal tissue is vulnerable to biologic damage induced by mechanical overload and adipokines. Of particular interest, this is the first study demonstrating that meniscal tissue is more catabolically sensitive to adipokines than cartilage tissue. These results provide evidence that obesity-driven degradation of knee joint tissues could be biochemically mediated and suggest meniscal degradation as a possible early event in osteoarthritis development.
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