MOBILITY ENGINEERING Produced by SAE Media Group
MOBILITY ENGINEERING
Magazines
Magazine cover

Current Issue

Archives

Magazine cover

Current Issue

Archives

Magazine cover

Current Issue

Archives

Magazine cover

Current Issue

Archives

Genetic Studies of Responses of Bones to Mechanical Stresses

Responses differ among individuals and are strongly affected by genetic factors.

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

Topics:
Biological sciences Medical Research and development
This Brief includes a Technical Support Package (TSP).
Document cover
Genetic Studies of Responses of Bones to Mechanical Stresses

(reference ARL-0039) is currently available for download from the TSP library.

Don't have an account?

More From SAE Media Group

    Magazine cover
    Defense Tech Briefs Magazine

    This article first appeared in the February, 2009 issue of Defense Tech Briefs Magazine (Vol. 3 No. 1).

    Read more articles from this issue here.

    Read more articles from the archives here.

    Overview

    The document is an annual report titled "Molecular Genetic Studies of Bone Mechanical Strain and of Pedigrees with Very High Bone Density," authored by Dr. Subburaman Mohan and prepared for the U.S. Army Medical Research and Materiel Command. The report covers research conducted from October 31, 2006, to October 30, 2007, under Award Number DAMD17-01-1-0744.

    The primary objective of the research is to investigate the genetic factors that mediate the skeletal response to mechanical stress, particularly focusing on bone mechanical strain. The study aims to identify genes and their functions that contribute to variations in bone density and response to mechanical loading. Two main hypotheses guide the research:

    1. Quantitative Trait Loci (QTL) Analysis: This involves using a four-point bending technique on two strains of mice that exhibit significant differences in their loading responses. The goal is to identify chromosomal locations of genes associated with variations in skeletal response to mechanical loading.

    2. Microarray and Tyrosine Phosphorylation Studies: This approach utilizes bone cells derived from inbred strains of mice to identify key signaling genes and pathways that influence bone cell responses to mechanical strain and fluid flow shear stress.

    The report outlines specific objectives for the first year of the continuation proposal, including the crossbreeding of two mouse strains (a poor responder and a good responder) to produce F1 mice for further study. The research has made considerable progress, resulting in one published manuscript and two abstracts during the reporting period.

    The document emphasizes the importance of understanding the molecular mechanisms underlying bone formation and the genetic basis of bone density variations. The findings are expected to contribute to a better understanding of how mechanical stress affects bone health and may have implications for treating conditions related to bone density, such as osteoporosis.

    Overall, the report highlights the ongoing efforts in genetic research related to bone health, the methodologies employed, and the anticipated outcomes that could enhance the understanding of skeletal biology and its response to mechanical forces. The research is significant for both scientific advancement and potential clinical applications in bone health management.

    Top Stories

    INSIDERLighting Technology

    Feature Image Using Ultrabright X-Rays to Test Materials for Ultrafast Aircraft

    INSIDERManufacturing & Prototyping

    Feature Image New 3D-Printable Nanocomposite Prevents Overheating in Military Electronics

    INSIDERDefense

    Feature Image F-22 Pilot Controls Drone With Tablet

    Technology ReportAR/AI

    Feature Image Talking SDVs and Zonal Architecture with TE Connectivity

    INSIDERManufacturing & Prototyping

    Feature Image New Defense Department Program Seeks 300,000 Drones From Industry by 2027

    INSIDERAerospace

    Feature Image Anduril Completes First Semi-Autonomous Flight of CCA Prototype

    Webcasts