Aging and associated age-related diseases are becoming increasingly important as the percentage of the population comprised by the elderly increases. Osteoarthritis (OA) is a chronic disease which affects diarthrodial joints predominantly in older individuals and is manifested by loss of articular cartilage which often progresses to the point of total joint destruction. Among various parameters which determine the onset and progression of osteoarthritis, age appears to be the greatest risk factor. At present, however, it is still unclear whether aging and osteoarthritis are a continuum or whether this disease is precipitated by biological factors not directly tied to aging. There remain important questions as to what defines """"""""normal"""""""" aging, and how much of the pathogenesis of osteoarthritis results from non-age-related causative mechanisms. Studies from our laboratories and others suggest that osteoarthritis pathology is characterized by decreased cellularity and/or cell viability and increased fibrillation. These changes are regulated by molecules that mediate both catabolic and anabolic responses in chondrocytes. Employing an experimentally induced osteoarthritis model in mature rabbits, we demonstrated an up-regulation of catabolic mediators such as MMP-3, IL-1beta and nitric oxide in cartilage and meniscus. These changes correlated with the observed development of OA pathology. To date, however, a systematic correlation of specific molecular mediators with age-related OA pathology has yet to be elucidated. We propose that changes in cartilage cellularity/viability, and in expression of matrix metalloproteinases (MMPs), metabolic and apoptotic regulators (i.e. cytokines and nitric oxide), and extracellular matrix (ECM) structural molecules play a leading role in the induction and maintenance of osteoarthritis during aging. To delineate the role of these molecules in the pathology of developing OA and distinguish between age-related and non-age-related effects, we will study mature and aged rabbits in an animal model of experimentally induced OA, i.e. anterior cruciate ligament transection. In a parallel study we will document human age-related joint pathology which will help us differentiate age-related osteoarthritic changes from experimentally induced effects. We also propose to characterize the role of a specific anabolic (TGF-beta1) and a catabolic (PTHrP) mediator on chondrocyte metabolism and function in an in vivo aged-animal model of osteochondral defect repair.
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