This is a revised application for a proposed research project that has, as its central goal, determining the importance of interleukin-6 (IL-6) dysregulation in the pathogenesis of post menopausal osteoporosis. Substantial changes include a better description of the methods of quantifying IL-6 expression and more substantial preliminary results. The project has been modified in other ways in response to prior review and the applicants believe that this is a significantly stronger proposal. The laboratory has focused on various aspects of age- associated immune dysfunction for the past decade. They have found that one molecule, Interleukin-6 (IL-6), is particularly interesting because its expression increases with age. They feel it may contribute to certain age-related maladies including osteoporosis. It is their hypothesis that estrogen inhibits IL-6 gene expression in bone and that one reason for the rise in IL-6 levels in postmenopausal women is the loss of the inhibitory influence of estrogen. Recently it has been shown that IL-6 enhances osteoclast formation in rodents. Therefore, one mechanism whereby estrogen deficiency might result in bone resorption is by the associated rise in IL-6 and increased osteoclast activity. In the current research the investigators intend to explore this hypothesis in rhesus monkeys. Twenty middle-aged (10-15 years) female monkeys will be subjected to oophorectomy and ten of these will have estrogen replacement. Five additional age-matched controls will be followed without oophorectomy (sham-operated controls). Blood, urine and bone specimens will be obtained and dual energy x-ray absorptiometry (DXA) will be used to assess bone mineral density. Furthermore, the level of IL-6 gene expression by osteoblasts and other bone cells in the various bone envelopes will be analyzed in the context of estrogen status. IL-6 expression will also be correlated with bone mineral content (DXA), bone strength and histomorphometry. If their hypotheses are true, they will have shown in a primate model that IL-6 expression in cancellous and endocortical bone envelopes (but perhaps not in Haversian envelopes) is regulated by estrogen and that when estrogen levels are low, increased bone turnover and decreased bone strength is the result. This research will also be of value because it will provide useful longitudinal data on bone density, histomorphometry and bone strength in this important animal model.
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