This is an exploratory project with the goal of establishing whether so-called primary cilia on cells and/or proteins needed for their assembly and function are essential for skeletal development and postnatal growth. Work is also proposed to test the hypothesis that primary cilia are required for the normal remodeling response of skeletal tissues to mechanical stimulation. The studies are prompted by recent discoveries that primary cilia and signaling molecules associated with them serve as receptors on many cells, in worms and flies as well as in mice and humans, and that mutations in genes coding for proteins in primary cilia can cause skeletal defects in addition to abnormalities in internal organs. The investigators plan to combine genetic and other experimental studies in mice with biochemical analyses of cultured organs and cells derived from mice with mutations in genes that affect the formation or function of primary cilia. Through the studies, the investigators aim at establishing (1) whether primary cilia are needed for the formation and function of growth plates in long bones, (2) whether they also are needed for development of the normal pattern of bones in limbs, and finally, (3) whether the normal response of skeletal tissues to mechanical stimulation requires the presence of primary cilia on the cells in these tissues. The studies are likely to generate new and exciting insights into mechanisms for bone development and maintenance and the molecular machinery that regulates the response of bones to gravity and exercise. The studies may help define new targets for drugs aimed at reversing the loss of bone substance during aging and in osteoporosis or drugs that may accelerate bone loss in diseases with excess accumulation of bone substance, such as osteopetrosis.
