Molecular Genetic Studies of Bone Mechanical Strain and of Pedigrees with Very High Bone Density
LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION REDLANDS CA
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Our studies address the medical problem of stress fractures in the military as stress fractures are one of the most common and potentially debilitating overuse injuries experienced in the military recruit population. The overall hypothesis that we are addressing in this study is that state of the art molecular genetic approaches can identify the genes and their pathways responsible for extreme differences in skeletal anabolic response to mechanical strain. During the funding period, we have used state-of-the-art technologies to identify the genetic components that contribute to the extreme differences in the skeletal anabolic response to mechanical strain in two inbred strains of mice. The candidate genes identified using QTL and whole genome microarray approaches were then validated using siRNA technique in vitro to suppress expression of genes and evaluating biological response to fluid flow shear strain and targeted or conditional disruption of gene of interest in vivo and evaluating skeletal anabolic response to mechanical loading. Our QTL and whole genome microarray studies revealed that several genetic loci in different chromosomes contribute to the variation in skeletal anabolic response to loading in C57BL6J B6 and C3HHeJ strains of mice. In vitro and in vivo approaches utilizing targeted disruption of genes have identified involvement of IGF-I, integrin and BMP signaling pathways in mechanical loading process. Future validation of mechanosensitive genes in genetic association studies will determine their utility to develop genetic screens to identify individuals who are at increased risk of stress fractures.
- Anatomy and Physiology
- Medicine and Medical Research