Osteoporosis, skeletal fragility, and fracture are well-known pathological conditions associated with aging. The ability of bone to resist fracture, i.e. bone quality, can be viewed as a composite of phenotypic traits, each under polygenic and environmental regulation. The principal aim of this study is to positively identify chromosomal regions (termed quantitative trait loci, or QTLs) that contain genes influencing bone quality across the lifespan. The long-term goal is to elucidate the causal fields created by genes, environment, gene-gene, and gene-environment interactions that ultimately dictate the quality of our bones in old age. Phenotypic traits encompassing bone morphology, composition, and mechanical performance will be assessed in two types of descendents from crosses of C57BL/6 (B6) and DBN2J (D2) inbred strains of mice: (a) a BXD F2 intercross, and (b) twenty-two different BXD recombinant inbred (RI) strains. Traits related to muscle mass, activity, and general health will also be quantitatively measured. Over twenty-five hundred animals, equally divided between male and female, will be examined at three ages representative of young adulthood (150 days), midlife (450 days), and advanced age (750 days). Quantitative bone quality data will be analyzed against corresponding genetic marker information from each individual F2 animal and from pre-existing RI databases. Univariate screening will be used to conduct genome-wide scans for QTLs associated with bone quality and potentially useful marker arrays correlating with distinct skeletal phenotypes will be identified. Regressions will be performed between skeletal phenotypes and phenotypes from other domains to determine relationships across physiologic systems and multivariate analyses will be conducted to identify QTLs that have pleiotropic effects on the correlated phenotypes. QTLs strongly associated with age-related reductions in bone quality will be sought by deriving novel phenotypes of bone loss from the longitudinal data.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021559-02
Application #
6668495
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Carrington, Jill L
Project Start
2002-09-30
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$250,192
Indirect Cost
Name
Pennsylvania State University
Department
Miscellaneous
Type
Schools of Allied Health Profes
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Lang, Dean H; Conroy, David E; Lionikas, Arimantas et al. (2009) Bone, muscle, and physical activity: structural equation modeling of relationships and genetic influence with age. J Bone Miner Res 24:1608-17
Sharkey, Neil A; Lang, Dean H (2007) Genes in context: probing the genetics of fracture resistance. Exerc Sport Sci Rev 35:86-96
Bower, Abbey L; Lang, Dean H; Vogler, George P et al. (2006) QTL analysis of trabecular bone in BXD F2 and RI mice. J Bone Miner Res 21:1267-75
Lang, Dean H; Sharkey, Neil A; Lionikas, Arimantas et al. (2005) Adjusting data to body size: a comparison of methods as applied to quantitative trait loci analysis of musculoskeletal phenotypes. J Bone Miner Res 20:748-57
Lang, Dean H; Sharkey, Neil A; Mack, Holly A et al. (2005) Quantitative trait loci analysis of structural and material skeletal phenotypes in C57BL/6J and DBA/2 second-generation and recombinant inbred mice. J Bone Miner Res 20:88-99