Genetics of Osteoporosis - Studies on bone size, structure and strength in the rat

Abstract: Osteoporosis is characterized by decreased bone mineral density (BMD) leading to reduced bone strength and increased fracture risk. Several heritable components affect a bone’s ability to resist fracture, including size, structure and strength; therefore identification of the genes underlying several bone characteristics will help elucidate the pathogenesis of fracture risk. Dissection of the genetic determinants of osteoporosis has been more effective in animal models than in human populations due to the possibility of environmental control and minimization of genetic heterogeneity. The aim of this thesis was to identify quantitative trait loci (QTLs) affecting osteoporosis-related phenotypes in an F2 intercross between diabetic GK and non-diabetic F344 rats, differing in their mitochondrial (mt) DNA. For bone measurements, tibia were characterized using four different methods generating several skeletal determinants of fracture risk. Comprehensive analysis identified several chromosomal regions linked to bone size, structure and strength that were influenced by both sex- and reciprocal cross. A region on chromosome 1 was identified with linkage to several bone phenotypes and also fasting glucose, making this region as a strong candidate for the localisation of genes contributing to bone regulation and potentially type-2 diabetes. The observed interaction between nuclear QTLs for bone phenotypes and reciprocal cross, demonstrates a new interesting aspect when interpreting the genetics of phenotypes related to bone strength. Furthermore, preliminary studies suggest that this rat model can be a useful tool to delineate the genetics of type-2 diabetes and osteoporosis in conjunction with lifestyle factors such as high-fat diet.