Cartilage is one of the tissues with the highest frequency of age-related pathology and osteoarthritis not only represents the most frequent musculoskeletal disorder but also the most common disease in the aging population. One very remarkable change which occurs with aging of human articular cartilage is the profound loss in tissue cellularity. This corresponds to an age-related decline in growth factor responsiveness of human articular chondrocytes. IL-1 induced catabolic responses in chondrocytes represent central pathogenic events in osteoarthritis. IL-1 induces matrix metalloproteinases, other proinflammatory cytokines and inhibits extracellular matrix synthesis. IL-1 also inhibits chondrocyte proliferation. In preliminary studies we have shown that human articular chondrocytes and cartilage tissue but not synoviocytes or inflammatory cells from synovial effusions can be induced to produce NO. In chondrocytes NO synthesis has the characteristics of inducible NO synthase (iNOS) and NO can be induced by cytokines such as IL-1, TNF and LIF that cause connective tissue degradation but not by factors that induce chondrocyte proliferation and formation of extracellular matrix such as TGFBeta, PDGF or IGF-I. We cloned the cDNA encoding human chondrocytes inducible nitric oxide synthase (iNOS). The sequence is identical to that of the human hepatocyte iNOS. Signaling pathways that are utilized in the induction of iNOS have been identified. We have also demonstrated that NO can increase PGE2 production in chondrocytes and mediates the growth inhibitory effects of IL- l. Our most recent work has shown that NO is the major inducer of apoptosis in chondrocytes. We now propose to (I) evaluate the effects of NO on proliferation of normal adult human articular chondrocytes and determine whether chondrocyte-derived NO functions as a mediator of other growth inhibitory factors; (ii) study the production of NO during chondrocyte aging in vivo and in vitro and determine whether it contributes to the reduced proliferative responses by cells from older donors and during in vitro senescence. (iii) study the role of NO in chondrocyte aging by using IRF- knock-out-mice which are deficient in iNOS expression. These studies will generate insight into the role of NO in chondrocyte and cartilage aging and provide a basis for new concepts on osteoarthritis pathogenesis, prevention and treatment.
NIH ExPorter
NIH ExPorter