Progress has been reported in a continuing program of molecular genetic studies of the responses of bones to mechanical stresses. Prior studies in mice and humans had provided evidence that mechanical loading stimulates bone formation and that immobilization or loss of mechanical stimulation leads to decreasing bone formation and increasing bone loss. Other prior studies in humans and mice had demonstrated that bone anabolic response differs widely among individuals subjected to the same degree of mechanical loading. The initiation of the present studies was motivated by the conjecture that variations in bone anabolic response among individuals are attributable to differences in the transcription levels of genes; that is, they are genetically controlled.

One of the approaches often used to study the genetic regulation of an observed phenotype is mapping of quantitative trait loci (QTL). This approach has been well established in both human and mouse models and has revealed hundreds of chromosomal regions containing genes affecting such bone phenotypes as bone mass density (BMD), bone size, and bone strength. Earlier in this research program, traditional QTL [also denoted classical QTL (cQTL)] was used to identify several loci that regulate mass density and size in response to mechanical loading in a cross between two inbred strains of mice, one of which responds well, the other of which responds poorly to mechanical stress.

A number of studies in humans and animals have provided evidence that expression levels of genes are amenable for genetic analysis in search of loci associated with phenotypic variations. The resulting approach, denoted expression QTL (eQTL), offers several advantages: (1) it enables mapping of a QTL to a gene, indicating whether cis changes or trans factors are responsible for the different expression levels; (2) it enables one to identify genetic regions that directly control the expression levels of genes; and (3) it enables validation of chromosomal regions identified from cQTL and determination of whether these regions are responsible for differences in transcription levels of genes that, in turn, are responsible for differences, between the two strains of mice, in bone anabolic responses to mechanical loading. Recently, in one of the present studies, expression levels of bone marker genes were utilized as quantitative traits for the two strains of inbred mice in order to perform a genome-wide search of loci that regulate the bone anabolic response to mechanical loading. Key accomplishments of this eQTL study include (1) confirmation of the finding from the earlier cQTL study that chromosome 8 contains genes involved in increasing bone formation in response to mechanical loading; (2) identification, on chromosomes 16 and 19, of two QTLs involved in response to mechanical loading; and (3) a tentative finding that portions of chromosomes 4, 16, and 18 are responsible for both natural variations of the bone sialoprotein (BSP) and alkaline phosphatase (ALP) phenotypes and increases in these phenotypes in response to mechanical loading.

Another study in this research program involves in vitro experiments that have lead to the identification of (1) the leptin receptor (LEPR) gene as, potentially, a negative-mechanosensitivity gene and (2) the potential molecular mechanism by which LEPR acts to suppress the fluid-shear-stress-induced proliferation and differentiation of osteoblasts. The study also produced evidence that the LEPR in osteoblasts of the two strains of mice might have different functional activity and that this difference may be partly responsible for the differences in the bone anabolic responses to mechanical stresses in the two strains.

This work was done by Subburaman Mohan of the Loma Linda Veterans Association for Research and Education; Chandrasekhar Kesavan, Susanna Kapoor, K. H. W. Lau, S. Kapur, M. Amoui, and X. Wang of the Jerry L. Pettis Veterans Administration Medical Center; and David J. Baylink of Loma Linda University for the Army Research Laboratory.

ARL-0039


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Genetic Studies of Responses of Bones to Mechanical Stresses

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