Osteoporosis is a major public health problem The cellular events that regulate accrual of skeletal n:sss are poorly understood but bear importantly on the risk for osteoporosis. Thus, high peak adult bone mass reduces the subsequent risk for osteoporotic fracture. While it is known that most of the variance in peak adult bone mass is genetically determined, no genes have yet been identified as being key regulators of skeletal mass. We have recently observed that patients with Gitelman's syndrome, a genetic disorder resulting from inactivating mutations in the gene for the thiazide-sensitive Na-Cl co-transporter (NCCT), have a markedly increased bone density (BMD) at all skeletal sites. NCCT is expressed at in the kidney as well as in osteoblast-like cells. The mechanism for higher BMD in Gitelman's syndrome and thiazide therapy is not known. The goal of this proposal is to elucidate the role of the thiazide-sensitive Na-Cl c-transporter (NCCT) in bone and mineral metabolism using the NCCT knock-out mouse model for Gitelrnan's syndrome. We plan to verity the human findings of higher BMD in Gitelman's syndrome in the mouse model, evaluate the response to continuous and intermittent infusions of parathyroid hormone, and use bone culture systems from these animals to evaluate response to anabolic and catabolic stimuli. P30AR46032-02-0005 Intra articular fractures have been associated with the development of post-traumatic arthritis. Current articular cartilage models have focused on the development of osteoarthritis in the setting of joint instability, scarification, subfracture impaction, or articular stepoff. None have looked at the effect of the combination of cartilage impaction and articular incongruity, which more closely represents a true clinical fracture. The purpose of this pilot study is to create a fracture model that combines articular cartilage impaction and articular stepoff, and to demonstrate an amplifying relationship between these two factors. Twenty New Zealand white rabbits will be obtained. The tibial articular surface will be impacted with a 90% subfracture force, then cut in a controlled manner, and then fixed at either 0mm or 2mm of stepoff. After being sacrificed at 6 months, evaluation of the progressive articular surface degeneration will include gross assessment, radiographic assessment, histologic staining with Safranin-O, and biochemical analysis for proteoglycan content by uronic acid assay. We propose that the impaction injury that occurs to the articular cartilage will magnify the effect of articular stepoff, and will lead to more advanced arthritis. The model developed in this pilot project will form the foundation for further study on the effect of impaction on the rate of development of arthritis, the effect of progressive stepoffs on the development of arthritis, and collaborative cellular studies on the effect of impact and abnormal articular loading on chondrocyte function.
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