| The overarching goal of this research is to identify the biologic role of the meniscus in the development of osteoarthritis. We hypothesized that inflammatory factors associated with joint injury would stimulate menisci to increase production of matrix-degrading enzymes, cytokines and chemokines, which could contribute to joint tissue destruction and subsequent development of osteoarthritis. We examined meniscus pathology in established osteoarthritis, characterized the alterations in meniscus cell processes between normal and osteoarthritic menisci, and explored potential pathways involved in osteoarthritis pathogenesis including a novel pathway proposed to mediate osteoarthritis development.;Vervet monkeys were used to examine meniscus pathology as part of the natural history of osteoarthritis and demonstrated osteoarthritic changes. Aged and degenerative menisci secreted increased matrix-metalloproteinases (MMPs) and cytokines and chemokines. To explore osteoarthritis pathogenesis in the human meniscus, meniscus cells were collected from normal tissue donors and patients undergoing total knee arthroplasty. Meniscus cells responded to pro-inflammatory stimulation with increased production of catabolic factors, including MMPs and cytokines and chemokines. Pro-inflammatory stimulation acted at least in part through the nuclear factor-kappaB (NF-kappaB) pathway. The hypoxia-inducible factor (HIF) family was then evaluated to determine the HIF family contribution to osteoarthritis pathogenesis in human meniscus cells and evaluate them in the context of a mouse surgical model of osteoarthritis. Human meniscus cells did express HIF family genes, but we could not substantiate a role for the HIF family as a primary regulator of osteoarthritic changes in the meniscus. Heterozygous deletion of the HIF-2alpha gene, Epas1, in mice did not provide resistance to surgically induced osteoarthritis.;The meniscus likely has a biologic role in the development of osteoarthritis. Pro-inflammatory stimulation and catabolic alterations in the meniscus produce a disease process that appears to be complementary to that of articular chondrocytes. The role of the HIF pathway in promoting osteoarthritic changes in the meniscus is not clear and requires further investigation. Continued exploration into the biologic responses of the meniscus to injury and may yield improved repairs and provide opportunities for tissue engineering and may ultimately aid in prevention or attenuation of osteoarthritis. |
