GENETIC AND DYNAMIC ANALYSES OF PEAK BONE DENSITY

Summary

Principal Investigator: Wesley Beamer
Affiliation: The Jackson Laboratory
Country: USA
Abstract: DESCRIPTION: (Adapted from investigator's abstract) Osteoporosis is a bone wasting disease that afflicts about 20 million Americans. Osteoporotic fractures occur when bone density (BD) falls below the fracture threshold, a change dependent upon the peak bone density achieved by young adulthood and the subsequent net bone loss after the menopause. Up to 70% of the variation in peak BD within is inheritable. Recognizing that it is important to identify genes responsible for peak BD, the applicants initiated studies in genetically-defined inbred strains of mice. This led to discovery of a genetic model with two inbred mouse strains, C57BL/6J and C3H/HeJ, with highly significant differences in vertebral (11%), tibial (34%), and femoral (54%) BD. By using a combination of pQCT, serum and urine biochemical assays of bone formation (BF) and bone resorption (BR), and histomorphometry, they have obtained the following preliminary data. The C3H/HeJ mice (highest BD) differed from the C57BL/6J mice in the following manners: 1) reduced medullary cavity volume and increased cortical thickness; 2) increased metaphyseal trabecular BD, indicating interstrain differences occur at the endosteum and at trabecular bone: 3) decreased serum osteocalcin, serum skeletal alkaline phosphatase, and urine crosslinks/creatinine at 2 months of age; and 4) decreased osteoclast number at both endosteal cortex and trabecular bone at 2 months of age, suggesting that at this time point, decreased BR contributed to the interstrain difference in BD. Based on this preliminary data, they have advanced two hypotheses: 1) the interstrain difference in BD is determined by a fixed number of genes that can be mapped; and 2) the interstrain difference in BD is a consequence of gene effects on endosteal/trabecular BF or endosteal/trabecular BR, or both. To test the first hypothesis, a combination of genetic crosses and molecular analytic approaches will be applied to: 1) intercross F2 progeny for quantitative trait loci analyses (QTL) with the C57BL/6J and C3H/HeJ strains, plus recombinant inbred (RI) strain analyses using the BXH RI strain set derived from C57BL/6J and C3H/HeJ progenitors; and 2) recombinant congenic (RC) strains plus backcrosses of RC strains with C57BL/6J. Correlation of BD phenotypes with segregating DNA polymorphisms will establish genetic linkage, estimate the number of genes involved with interstrain bone density differences, genetically order bone regulatory genes with major and important modifier effects, define mode of inheritance for each gene, and evaluate parent-of-origin effects on BD. To test the second hypothesis, longitudinal studies will be conducted during development of peak BD in the two inbred mouse strains, applying methodologies for BD, bone histomorphometry, and bone biochemical assays. The data obtained will be analyzed: 1) to quantitatively describe the BF and BR mechanisms that account for the increase in BD within each mouse strain; and 2) to determine the differences in BF and BR that account for the difference in peak BD between the mouse strains. Ultimately, the applicants propose to correlate the phenotypic modeling mechanisms disclosed by their dynamic studies of bone modeling with the genes mapped in the first Aim.
Funding Period: 1996-09-01 - 2001-04-30
more information: NIH RePORT

Top Publications

  1. pmc Quantitative trait loci for tibial bone strength in C57BL/6J and C3H/HeJ inbred strains of mice
    Feng Jiao
    Department of Orthopedic Surgery Campbell Clinic, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    J Genet 89:21-7. 2010
  2. pmc Multiple quantitative trait loci for cortical and trabecular bone regulation map to mid-distal mouse chromosome 4 that shares linkage homology to human chromosome 1p36
    Wesley G Beamer
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Bone Miner Res 27:47-57. 2012
  3. pmc Quantitative trait loci, genes, and polymorphisms that regulate bone mineral density in mouse
    Qing Xiong
    Department of Orthopaedic Surgery Campbell Clinic and Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Genomics 93:401-14. 2009
  4. pmc A novel spontaneous mutation of Irs1 in mice results in hyperinsulinemia, reduced growth, low bone mass and impaired adipogenesis
    Victoria E DeMambro
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    J Endocrinol 204:241-53. 2010
  5. pmc BMD regulation on mouse distal chromosome 1, candidate genes, and response to ovariectomy or dietary fat
    Wesley G Beamer
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Bone Miner Res 26:88-99. 2011
  6. pmc Initiation of BMP2 signaling in domains on the plasma membrane
    Jeremy Bonor
    Department of Biological Sciences, University of Delaware, Newark, DE, USA
    J Cell Physiol 227:2880-8. 2012
  7. pmc Bone morphogenetic protein receptor type Ia localization causes increased BMP2 signaling in mice exhibiting increased peak bone mass phenotype
    Beth Bragdon
    Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
    J Cell Physiol 227:2870-9. 2012
  8. ncbi Genetic variation in femur extrinsic strength in 29 different inbred strains of mice is dependent on variations in femur cross-sectional geometry and bone density
    Jon E Wergedal
    Musculoskeletal Disease Center, J L Pettis Memorial V A Medical Center and Department of Medicine, Loma Linda University, Loma Linda, CA 92357, USA
    Bone 36:111-22. 2005

Scientific Experts

Detail Information

Publications8

  1. pmc Quantitative trait loci for tibial bone strength in C57BL/6J and C3H/HeJ inbred strains of mice
    Feng Jiao
    Department of Orthopedic Surgery Campbell Clinic, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    J Genet 89:21-7. 2010
    ..8 and represents 60% of the variation of bone strength; and (v) four QTLs of stiffness (chromosomes 2, 11, 15 and 19) have been identified...
  2. pmc Multiple quantitative trait loci for cortical and trabecular bone regulation map to mid-distal mouse chromosome 4 that shares linkage homology to human chromosome 1p36
    Wesley G Beamer
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Bone Miner Res 27:47-57. 2012
    ....
  3. pmc Quantitative trait loci, genes, and polymorphisms that regulate bone mineral density in mouse
    Qing Xiong
    Department of Orthopaedic Surgery Campbell Clinic and Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Genomics 93:401-14. 2009
    ..These data could facilitate more rapid and comprehensive identification of causal genes underlying the determination of BMD in mouse and provide new insights into how BMD is regulated in humans...
  4. pmc A novel spontaneous mutation of Irs1 in mice results in hyperinsulinemia, reduced growth, low bone mass and impaired adipogenesis
    Victoria E DeMambro
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    J Endocrinol 204:241-53. 2010
    ..Changes in the heterozygous Irs1(+)(/sml) mice raise the possibility that similar mutations in humans are associated with short stature or osteoporosis...
  5. pmc BMD regulation on mouse distal chromosome 1, candidate genes, and response to ovariectomy or dietary fat
    Wesley G Beamer
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    J Bone Miner Res 26:88-99. 2011
    ..In conclusion, our data suggest that osteoblasts are the cellular target of gene action and that AC084073.22 is the best candidate for female BMD regulation in the distal region of mouse Chr 1...
  6. pmc Initiation of BMP2 signaling in domains on the plasma membrane
    Jeremy Bonor
    Department of Biological Sciences, University of Delaware, Newark, DE, USA
    J Cell Physiol 227:2880-8. 2012
    ..This suggests caveolae are necessary for the initiation of Smad signaling. We propose an extension of the current model of BMP2 signaling, in which the initiation of Smad signaling is mediated by BMPRs in caveolae...
  7. pmc Bone morphogenetic protein receptor type Ia localization causes increased BMP2 signaling in mice exhibiting increased peak bone mass phenotype
    Beth Bragdon
    Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
    J Cell Physiol 227:2870-9. 2012
    ..C3H-1-12 congenic and (ii) contributes to increase BMD of the B6.C3H-1-12 compared to the C57BL/6J control mice...
  8. ncbi Genetic variation in femur extrinsic strength in 29 different inbred strains of mice is dependent on variations in femur cross-sectional geometry and bone density
    Jon E Wergedal
    Musculoskeletal Disease Center, J L Pettis Memorial V A Medical Center and Department of Medicine, Loma Linda University, Loma Linda, CA 92357, USA
    Bone 36:111-22. 2005
    ..These studies identify inbred mouse strains suitable for future studies identifying genes regulating bone geometry and mechanical properties...