Quantitative trait loci affecting peak bone mineral density in mice

Klein, Robert F.; Mitchell, Steve R.; Phillips, Tamara J.; Belknap, John K.; Orwoll, Eric S.

Affiliations

¹Bone and Mineral Research Unit, Department of Medicine, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon, U.S.A.

²Portland Alcohol Research Center and Department of Behavioral Neuroscience, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon, U.S.A.

Abstract

Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations, and effects of the individual genes contributing to natural variation in this trait are all unknown. Experimental animal models provide a means to circumvent complicating environmental factors, and the development of dense genetic maps based on molecular markers now provides opportunities to resolve quantitative genetic variation into individual regions of the genome influencing a given trait (quantitative trait loci, QTL). To begin to identify the heritable determinants of BMD, we have examined genetically distinct laboratory mouse strains raised under strict environmental control. Mouse whole-body bone mineral content by dual-energy X-ray absorptiometry (DXA) correlated strongly with skeletal calcium content by ashing, and peak whole-body BMD by DXA in female mice occurred at ∼80–90 days of age. We therefore determined mean body weight and peak whole body BMD values in 12-week-old female mice from a panel of 24 recombinant inbred (RI) BXD strains, derived from a cross between C57BL/6 and DBA/2 progenitors. The distribution of body weight and BMD values among the strains clearly indicated the presence of strong genetic influences on both of these traits, with an estimated narrow sense heritability of 60% and 35%, respectively. The patterns of differences in body weight and peak whole body BMD in the BXD strains were then integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL. After correction for redundancy among the significant correlations, QTL analysis of the BXD RI strain series provisionally identified 10 chromosomal sites linked to peak bone mass development in the female. Several of the identified sites map near genes encoding hormones, structural proteins, and cell surface receptors that are intricately involved in skeletal homeostasis. Four QTL for body weight were also identified. One of these loci was also strongly linked to inherited variation in BMD. This finding suggests that body weight and peak BMD may be influenced by linked genes or perhaps by common genes with pleiotropic effects. Our phenotyping in the RI BXD strains has allowed us to map a number of specific genetic loci strongly related to the acquisition of peak BMD. Confirmation of these findings will likely result in the understanding of which genes control skeletal health.

Links

DOI: 10.1359/jbmr.1998.13.11.1648

PubMed: 9797472

WoS: 000076526500002

History

Received: 1997-12-23

Revised: 1998-04-24

Accepted: 1998-08-13

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2002	Robling AG, Turner CH. Mechanotransduction in bone: genetic effects on mechanosensitivity in mice. Bone. November 2002;31(5):562-569.
2003	Ferguson VL, Ayers RA, Bateman TA, Simske SJ. Bone development and age-related bone loss in male C57BL/6J mice. Bone. March 2003;32(3):387-398.
2008	Chen H, Zhou X, Washimi Y, Shoumura S. Three-dimensional microstructure of the bone in a hamster model of senile osteoporosis. Bone. September 2008;43(3):494-500.
2000	Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. April 2000;21(2):115-137.
2000	Turner CH, Hsieh Y, Müller R, Bouxsein ML, Baylink DJ, Rosen CJ, Grynpas MD, Donahue LR, Beamer WG. Genetic regulation of cortical and trabecular bone strength and microstructure in inbred strains of mice. J Bone Miner Res. June 2000;15(6):1126-1131.
2001	Beamer WG, Shultz KL, Donahue LR, Churchill GA, Sen S, Wergedal JR, Baylink DJ, Rosen CJ. Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J Bone Miner Res. July 2001;16(7):1195-1206.
2001	Jepsen KJ, Pennington DE, Lee Y, Warman M, Nadeau J. Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice. J Bone Miner Res. October 2001;16(10):1854-1862.
2003	Amblard D, Lafage-Proust M-H, Laib A, Thomas T, Rüegsegger P, Alexandre C, Vico L. Tail suspension induces bone loss in skeletally mature mice in the C57BL/6J strain but not in the C3H/HeJ strain. J Bone Miner Res. March 2003;18(3):561-569.
2005	Bouxsein ML, Myers KS, Shultz KL, Donahue LR, Rosen CJ, Beamer WG. Ovariectomy‐induced bone loss varies among inbred strains of mice. J Bone Miner Res. July 2005;20(7):1085-1092.
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2007	Schneider P. Ultrastructural Phenotyping of Murine Bone Using Synchrotron Micro- and Nano-Computed Tomography [PhD thesis]. Swiss Federal Institute of Technology Zürich; 2007.
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2008	Price C. Systems Based Approaches to Identifying How Genetically Varying Skeletal Growth Affects Skeletal Functionality and Fragility [PhD thesis]. Mount Sinai School of Medicine; 2008.
2009	Bower AL. An Investigation of Trabecular Bone Morphology [PhD thesis]. State College, PA: Pennsylvania State University; December 2009.
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2007	Wallace JM III. Investigating the Inbred Strain-Specific Response to Biglycan-Deficiency and Exercise: A Study in Genetically-Mediated Skeletal Adaptation [PhD thesis]. University of Michigan; 2007.