The Effects of CFTR Deficiency on Metabolic Bone Disease

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DESCRIPTION (provided by applicant): As a trained physician in the field of pediatric endocrine, I have directed my clinical and research specialization on the endocrine disorders associated with cystic fibrosis (CF). This work is the product of multiple years of self-directed and mentored training in both the laboratory and clinical setting. It is through these efforts that I have collected evidence to support this proposal. Recent data suggests that an underlying defect exists in bone metabolism of cystic fibrosis transmembrane conductance regulator (CFTR) deficient mice. This echoes recent findings identifying CFTR in cells responsible for human bone metabolism. CF has a pronounced incidence of osteoporosis. Additionally, this increased disease rate has grown as the life expectancy increased. Although a limited number of potential mechanisms underlying this observation have been identified and explored, its pathogenesis remains largely unknown. It is our belief that defects in bone metabolism exist secondary to absence of CFTR function. Within this model, the proposed mechanism of action involves differentiation and regulation of cells responsible for bone turnover; namely osteoblasts and osteoclasts. The model also concedes other influences, such as absence of anabolic stimuli found in both clinical CF and the Cftr-deficient (Cftr-/-) mouse, would contribute and worsen the bone mineral disease profile. To identify involvement of CFTR in relation to bone mineral disease, we will test the hypothesis that the absence of CFTR interferes with normal evolution and function of cells responsible for bone metabolism. This hypothesis will be tested by performance of three specific aims. The first aim addresses the impact of CFTR on osteoblast and osteoclast cellular activity at baseline in Cftr-deficient mice. The second aim determines the contribution of isolated CFTR deficiency, through use of a CFTR cell type-specific conditional knockout in osteoblasts and osteoclasts. The third aim further delineates the systemic role of CFTR deficiency, after correction at the osteoblast and osteoclast level through bone marrow transfer. This proposed career development award will provide the necessary time allotment and additional training to launch my work into the field of metabolic bone disease. Additionally, the proposed plan will lay indispensable groundwork into the understanding of CF bone disease and the impact of CFTR on bone metabolism.