Preventing fractures is an important health care challenge, as fragility fractures are already common and will become more so as the US population continues to age. Susceptibility to fragility fractures varies widely with genetic factors accounting for ~50% of this variation. Fracture risk is determined by peak bone mass and skeletal morphology achieved in young adulthood and the rate and extent of bone loss thereafter. Mice provide a valuable animal model for studying skeletal genetics. Several groups have identified genetic loci that contribute to bone strength in the mouse. We have mapped biomechanical performance quantitative trait loci (QTLs) in intercrosses of HcB- 13 x HcB-14 and HcB-8 x HcB 23 recombinant congenic mice, with QTLs located on chromosomes 1, 2, 3, 4, 6, 10, and X. We hypothesize that these QTLs will retain demonstrable effects on the skeleton following isolation as fully congenic strains harboring individual donor segments ultimately derived from HcB series'common C57BL/10ScSnA ancestor on a C3H/DiSnA background. We further hypothesize that historical recombination events will facilitate our efforts to identify the genes underlying the QTLs, as has been the case on chromosome 4. The project includes 3 specific aims. First, we will construct 4 congenic strains harboring C57BL/10ScSnA-derived donor segments, targeting chromosomes with the most robust mapped QTLs. Second, we will phenotype incipient congenics at N5F2 and newly established congenics at N10F2. The donor segment genotype's effect on phenotype in the context of the C3H/DiSnA background will thus be assessed. Third, we will determine the genetic fine structure of the parental strains HcB/8, HcB/13, HcB/14, HcB/23, and the incipient congenics and work toward identifying the responsible genes. Proceeding from a mapped QTL to an identified gene usually requires several intervening steps, for which congenic strains are particularly valuable. The first is to confirm that the locus retains its effect when isolated. The next is to exploit crossovers to subdivide the candidate interval for the responsible gene(s). The HcB strains have undergone recombination events that will prove useful at this stage of analysis. These efforts culminate in functional analyses of a restricted set of candidate genes. The congenic strains will also prove valuable in studying epistatic interactions between the individual QTLs. Identifying genes that affect bone biomechanical performance and understanding their interactions will offer the potential to design better measures to prevent fracture, regardless of whether these are related to aging, extreme loading conditions, other illnesses, or adverse effects from medications.

Public Health Relevance

We have mapped genes that contribute to differences in bone strength and related properties in mice. We will isolate the chromosome segments that contain these genes by a standard congenic breeding program. We will confirm that the bone effects persist following the breeding program. We will perform additional genetic experiments to identify the responsible genes.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Sharrock, William J
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Medical College of Wisconsin
Internal Medicine/Medicine
Schools of Medicine
United States
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Kristianto, Jasmin; Litscher, Suzanne J; Johnson, Michael G et al. (2016) Congenic Strains Confirm the Pleiotropic Effect of Chromosome 4 QTL on Mouse Femoral Geometry and Biomechanical Performance. PLoS One 11:e0148571
Meyer, Luisa A; Johnson, Michael G; Cullen, Diane M et al. (2016) Combined exposure to big endothelin-1 and mechanical loading in bovine sternal cores promotes osteogenesis. Bone 85:115-22
Blank, Robert D (2015) Dual-Energy X-ray Absorptiometry Image Resolution and TBS Precision. J Clin Densitom 18:143-4
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Yachoui, Ralph; Kristianto, Jasmin; Sitwala, Kajal et al. (2015) Role of Endothelin-1 in a Syndrome of Myelofibrosis and Osteosclerosis. J Clin Endocrinol Metab 100:3971-4
Blank, Robert D (2015) Spine-Hip Thickness Ratio and Diabetes. J Clin Densitom 18:455-6
Blank, Robert D (2015) System level genes or physiological adaptation? Bone 75:247-8
Blank, Robert D (2014) Bone and Muscle Pleiotropy: The Genetics of Associated Traits. Clin Rev Bone Miner Metab 12:61-65
Johnson, Michael G; Kristianto, Jasmin; Yuan, Baozhi et al. (2014) Big endothelin changes the cellular miRNA environment in TMOb osteoblasts and increases mineralization. Connect Tissue Res 55 Suppl 1:113-6
Muir, Alison M; Ren, Yinshi; Butz, Delana Hopkins et al. (2014) Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet 23:3085-101

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