Osteoporosis is a disease of progressive bone loss, leading to a weak and fracture prone skeleton. Osteoporosis is primarily a genetic disorder of low bone strength; however, strength cannot be measured in human in vivo. As a result, much remains to be discovered regarding the genetic basis of variation in strength. Here, we propose an innovative genetic analysis of a comprehensive suite of bone strength traits using Diversity Outbred (DO) mice. We will map high-resolution quantitative trait loci (QTL) for a wide array of bone traits including biomechanics, morphology, trabecular and cortical microarchitecture, marrow adiposity, dynamic histomorphometry and biomechanics. We will also use an innovative F1 in vivo validation strategy that mimics the complex genetic environment of QTL discovery using existing mutant mice or mice generated using CRISPR/Cas9. We will validate the role of Rhobtb3 and Soat1 in the regulation of bone strength and related traits. These genes were identified as candidates for bone strength QTL in a pilot study of CC and DO mice. Additional genes identified in the DO will be selected validated using existing mutant mice or through the development of mutants using CRISPR/Cas9. Our novel and innovative approach to gene discovery and validation has the potential to significantly increase our understanding of the basic biological processes that underlie variation in bone strength and lead to the discovery of novel therapeutic targets for the prevention and treatment of bone fragility.
Osteoporosis is a major public health burden. Current estimates indicate that 12 million people suffer from osteoporosis in the U.S. Bone strength is the ultimate predictor of osteoporotic fracture; however, little is known regarding its genetic basis. This research will identify genes that regulate bone strength, which may lead to the development of novel treatments for bone fragility.
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