Osteoporotic fractures are already a major health care problem, and with a steadily increasing geriatric population, they are projected to increase dramatically in the next few decades. Peak bone mass achieved in early adulthood is a major determinant of risk of osteoporotic fracture. Although lifestyle and environmental factors play a role in the achievement of peak bone mass, there is now clear evidence that genetic factors appear to be of great importance. Altogether, it has been calculated that up to 75% of bone mineral density is genetically determined, a contribution that appears to be polygenic in nature. The next essential step in genetic research on osteoporosis is to dissect this polygenic trait into discrete genetic factors. We have recently employed a new method for mapping genes which influence continuously varying traits such as bone mass. Such genes (or QTLs) were identified by first characterizing whole body BMD in a panel of 22 BXD/Ty recombinant inbred mouse strains, derived from a cross between C57BL/6J and DBA/2J inbred progenitor strains. The pattern of strain differences in whole body BMD was compared with a large data base of genetic markers, previously genotyped in the R1 strains, to generate candidate chromosome map sites for QTLs. We have identified seventeen provisional QTLs that may influence the acquisition of peak bone mass in female mice during skeletal growth. The focus of this proposal is to verify the provisional QTLs pertinent to the attainment of peak bone mass and develop new genetic animal models (congenic strains) for studying the effects of verified QTLs. As the mouse genome becomes ever more densely mapped due to the cumulative efforts of many groups, it will be easier to identify the location of BMD-relevant Tls more precisely. The mouse genome shows 80% linkage homology with portions of the human genome, making it likely that a QTL mapping result in the mouse will immediately suggest a map site in the human genome. Our proposal to map risk and protective genes and develop unique genetic animal models for isolating the effects of those genes, offers an important route to the possible identification of risk and protective genes in humans. This would allow prediction of individual, rather than statistical, risk, which in turn could lead to effective targeting of prevention-based treatment strategies to high-risk populations. Moreover, finding genes essential for peak bone mass development would offer tremendous insight into the biochemical and cellular basis of bone modeling and disorders of skeletal development.
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