Our goal for the competing renewal is to better understand how phenotypic covariation contributes to the genetic basis of skeletal fragility. Preliminary studies indicate that sets of adult traits are established during post-natal growth through functional interactions between matrix mineralization and bone surface expansions. Further, these functional relationships, which were consistent with current theories of how a strain-based biological feedback system operates, were deterministic of adult bone functionality and fragility. We hypothesize that phenotypic covariation is a genetically determined trait that simultaneously coordinates essential aspects of bone biology to match loading demands during development. We propose to test this hypothesis by mapping quantitative trait loci (QTLs) that alter phenotypic covariation (Aim 1) using C57BL/6J-ChrA/J Chromosome Substitution Strains (CSSs). Further, we hypothesize that allelic variants that alter phenotypic covariation result from an altered responsiveness to mechanical loading. We test this hypothesis by determining whether QTLs regulating phenotypic covariation and the adaptive response to exercise map to the same genomic regions (Aims 2, 3). Finding this association would mean that skeletal growth patterns could be used as a predictor of the responsiveness of bone to mechanical loading. Finally, we propose to systematically assess each level of structural hierarchy in order to assign biological functionality to the QTLs. To accomplish this, we combine QTL analyses with quantitative analyses of cellular activity and serum growth factors. Many CSSs will show alterations in a specific trait or a specific trait interaction, and this is expected to be associated with measurable changes in endocrine signals during growth. This genetic perturbation experiment thus allows us to seek a biological factor that acts as a common control coordinating cellular activities during growth (i.e., functional adaptation). We will focus on the GH/IGF axis since this is the primary determinant of post-natal growth. These studies will not only identify novel QTLs regulating trait interactions during growth, but the results should also provide important insight into how functional adaptation buffers the deleterious mechanical consequences of genetic variants leading to slender bone phenotypes.

Public Health Relevance

Growing a robust, fracture-resistant skeleton is a major goal for many fracture risk reduction strategies. By using a systems approach relating genetic variants to patterns of skeletal growth and to mechanical function, we propose to gain a new understanding of how genetic variation in growth leads to """"""""at-risk sets of adult traits"""""""" that increase fracture susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044927-14
Application #
8298943
Study Section
Special Emphasis Panel (ZRG1-MOSS-F (03))
Program Officer
Sharrock, William J
Project Start
1998-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$529,991
Indirect Cost
$147,800
Name
University of Michigan Ann Arbor
Department
Orthopedics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Scheller, Erica L; Doucette, Casey R; Learman, Brian S et al. (2015) Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nat Commun 6:7808
Jepsen, Karl J; Silva, Matthew J; Vashishth, Deepak et al. (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951-66
Schlecht, Stephen H; Bigelow, Erin M R; Jepsen, Karl J (2015) How Does Bone Strength Compare Across Sex, Site, and Ethnicity? Clin Orthop Relat Res 473:2540-7
Buchner, David A; Nadeau, Joseph H (2015) Contrasting genetic architectures in different mouse reference populations used for studying complex traits. Genome Res 25:775-91
Jepsen, Karl J; Bigelow, Erin M R; Schlecht, Stephen H (2015) Women Build Long Bones With Less Cortical Mass Relative to Body Size and Bone Size Compared With Men. Clin Orthop Relat Res 473:2530-9
Khoury, Basma M; Bigelow, Erin M R; Smith, Lauren M et al. (2015) The use of nano-computed tomography to enhance musculoskeletal research. Connect Tissue Res 56:106-19
Smith, Lauren M; Bigelow, Erin M R; Nolan, Bonnie T et al. (2014) Genetic perturbations that impair functional trait interactions lead to reduced bone strength and increased fragility in mice. Bone 67:130-8
Schlecht, Stephen H; Bigelow, Erin M R; Jepsen, Karl J (2014) Mapping the natural variation in whole bone stiffness and strength across skeletal sites. Bone 67:15-22
Jepsen, Karl J; Schlecht, Stephen H; Kozloff, Kenneth M (2014) Are we taking full advantage of the growing number of pharmacological treatment options for osteoporosis? Curr Opin Pharmacol 16:64-71
Jepsen, Karl J; Schlecht, Stephen H (2014) Biomechanical mechanisms: resolving the apparent conundrum of why individuals with type II diabetes show increased fracture incidence despite having normal BMD. J Bone Miner Res 29:784-6

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