This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Significance: The importance of this research lies in the link between aspects of cortical bone microstructure and increased risk of femoral neck fracture, a particularly debilitating condition that often results in long term mobility loss and even mortality. The osteonal remodeling process of bone maintenance and repair is an essential component of osteoporosis pathogenesis and is responsible for age-associated cortical bone loss and microstructural changes. Understanding the degree to which this process and the resulting microstructural changes are genetically regulated is an essential first step in providing a mechanism to identify individuals at greatest risk for fracture, so that courses of treatment can begin as early as possible, thereby increasing their efficacy. The proposed research is likely to produce new and useful information because it is the first study to formally test for genetic effects on the osteonal remodeling process and outcomes. It is being conducted using the only skeletal collection currently available in which this question can be addressed (i.e., pedigreed individuals). The expected result, based on other studies of bone biology, is that the baboon will be an appropriate model for the osteonal remodeling process in humans, and osteon morphology and distribution will show significant genetic effects. Osteonal remodeling results in microstructural age-related changes in cortical bone that contribute to risk of osteoporotic fracture. An understanding of the genetic regulation of this process will enable earlier identification of those individuals at greatest risk for cortical bone fracture, allowing for earlier implementation of prevention and treatment strategies. I propose to investigate the genetics of osteonal remodeling using a primate model. The hypotheses to be tested are: H1: The baboon provides an appropriate model for the osteonal remodeling process in humans, showing similar osteon morphology, remodeling dynamics, and age and sex effects. H2: Osteon morphology and remodeling dynamics are heritable in the baboon. Demonstrating heritability is essential for application to the National Institutes of Health for additional funding to increase the sample of genotyped baboons to conduct genome-wide linkage screens to identify the chromosomal regions and specific genes that contribute to normal variation in cortical bone microstructure. These data will also underpin future investigations of sex- and age-specific genetic effects.
The aims of this pilot project are to: 1) characterize normal variation, including age and sex effects, in osteon remodeling dynamics in the baboon, and 2) quantify the proportion of variation in osteon morphology and remodeling attributable in genes.
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