The Effect of Genetic Variation on Mouse Bone Strength

Osteoporosis is a heritable bone disease which is characterized by decreased bone mass and a deterioration in bone microarchitecture. This leads to a decrease in bone strength and therefore the risk of fracturing is greater in people who have been diagnosed as being osteoporotic. The mechanism by which osteoporosis is inherited is still unknown, as are the underlying microarchitectural causes of changes in bone strength. Without knowing more about these two mechanisms we cannot begin to develop more effective treatment plans or even a cure for this disease. The aim of this dissertation was to determine whether bone strength can be influenced by vascular canal microarchitecture and whether bone strength is a heritable trait, which is determined by specific quantitative trait loci. Using the CC founder strains and their F1 crosses in a diallel analysis we found that non-additive variance accounted for the same amount or more of the heritability than additive variance. Using the same CC mice we also found that BMD, canal connectivity, canal diameter, canal orientation, cortical area, cortical thickness, and percent porosity were all heritable determinants of bone strength. The bone strength measures used in this thesis were found to be highly correlated (0.702) and there was no statistical difference between methods (p=1.000). Employing the DO population we found a significant QTL for Imax on Chromosome 1 that is 1.43 cM wide and contained 19 candidate genes, of which Cacna1e looks the most promising. The QTL analysis for MaxF and BMD also found suggestive and near suggestive QTLs on Chromosome 1, which would indicate that Chromosome 1 is important in the genetic determination of bone strength.

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Year

Entry

1979

Lanyon LE, Bourn S. The influence of mechanical function on the development and remodeling of the tibia: an experimental study in sheep. J Bone Joint Surg. March 1979;61A(2):263-273.

1988

Schaffler MB, Burr DB. Stiffness of compact bone: effects of porosity and density. J Biomech. 1988;21(1):13-16.

1976

Wainwright SA, Biggs WD, Currey JD, Gosline JM. Mechanical Design in Organisms. London, UK: Edward Arnold; 1976.

1978

Uhthoff HK, Jaworski ZF. Bone loss in response to long-term immobilisation. J Bone Joint Surg. August 1978;60B(3):420-429.

2008

Buie HR, Moore CP, Boyd SK. Postpubertal architectural developmental patterns differ between the l3 vertebra and proximal tibia in three inbred strains of mice. J Bone Miner Res. 2008;23(12):2048-2059.