Osteoporosis is a complex disease, from a genetics standpoint. Bone mass and structure are highly heritable traits, but there are probably many genes that contribute to these traits. We have identified quantitative trait loci (QTL) in B6C3F2 mice that are linked to bone structure and strength. In addition, we have developed 11 congenic mouse lines, each of which contains a bone structure/strength QTL. Our preliminary studies demonstrate that the progenitor mouse strains (C57BL/6 and C3H/He) differ considerably in their skeletal response to mechanical loading. Furthermore, we demonstrated in a congenic mouse line, B6.C3H-4T, a significantly enhanced skeletal responsiveness to mechanical loading. Not surprisingly, B6.C3H-4T femurs have significantly larger cross-sectional size compared to B6 control femurs. This finding suggests that congenic mice can be used to identify genes that affect cellular mechanotransduction in bone. We have identified four congenic mouse lines (in addition to B6.C3H-4T) that have altered femoral crosssectional size. We propose to determine which of these congenic lines differ in skeletal mechanical loading response. We will then develop congenic sublines and complete fine mapping of the QTLs to isolate genes contributing to altered mechanotransduction. We will develop multiple sublines of congenic mice to genetically dissect each QTL region to better pinpoint the location on the chromosome contributing to femoral BMD and/or structure/strength phenotypes. In addition we will study osteoblasts isolated from congenic mouse lines to determine their responsiveness to mechanical stimuli and we will examine gene expression profiles in bones from congenic mice and in isolated osteoblasts in order to determine the genetic pathways that differ among the congenic lines.
| Castillo, Alesha B; Triplett, Jason W; Pavalko, Fredrick M et al. (2014) Estrogen receptor-? regulates mechanical signaling in primary osteoblasts. Am J Physiol Endocrinol Metab 306:E937-44 |
| Mantila Roosa, Sara M; Turner, Charles H; Liu, Yunlong (2012) Regulatory mechanisms in bone following mechanical loading. Gene Regul Syst Bio 6:43-53 |
| Mantila Roosa, Sara M; Liu, Yunlong; Turner, Charles H (2011) Alternative splicing in bone following mechanical loading. Bone 48:543-51 |
| Niziolek, Paul J; Farmer, Takeisha L; Cui, Yajun et al. (2011) High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. Bone 49:1010-9 |
| Mantila Roosa, Sara M; Liu, Yunlong; Turner, Charles H (2011) Gene expression patterns in bone following mechanical loading. J Bone Miner Res 26:100-12 |
| Chennimalai Kumar, Natarajan; Dantzig, Jonathan A; Jasiuk, Iwona M et al. (2010) Numerical modeling of long bone adaptation due to mechanical loading: correlation with experiments. Ann Biomed Eng 38:594-604 |
| Li, J; Zhao, L; Ferries, I K et al. (2010) Skeletal phenotype of mice with a null mutation in Cav 1.3 L-type calcium channel. J Musculoskelet Neuronal Interact 10:180-7 |
| Robling, Alexander G; Turner, Charles H (2009) Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr 19:319-38 |
| Niziolek, P J; Murthy, S; Ellis, S N et al. (2009) Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment. J Cell Physiol 221:579-85 |
| Li, Jiliang; Meyer, Rachel; Duncan, Randall L et al. (2009) P2X7 nucleotide receptor plays an important role in callus remodeling during fracture repair. Calcif Tissue Int 84:405-12 |
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