Etiology of cystic fibrosis bone disease

Yale University, New Haven CT

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Abstract

Median survival for people with Cystic Fibrosis (CF) has increased to ~30 years of age. As the number of people surviving well into adulthood has increased, aspects of the disease which impact quality of life have received prominent attention. One such complication is CF bone disease (CFBD), which is characterized by low bone density and increased fracture rate. The fundamental gene defects in CF are loss of function mutations in the CF transmembrane conductance regulator protein (CFTR) - a chloride channel involved in many cellular processes. However, CFBD remains minimally characterized and an understanding of its pathogenesis remains limited. Identifying the etiology of CFBD presents inherent difficulties because there are multiple factors, which can indirectly impact bone health and are often present in CF patients. However, published studies and our preliminary results .suggest a primary role for CFTR loss of function in CFBD. Our research objective is to characterize CFBD at the structural and cellular levels using a newly developed gut-corrected CF mouse model. These mice have functional correction of ileal goblet cell and crypt cell hyperplasia and cAMP-stimulated chloride secretion. This model thus provides a unique opportunity to look for direct effects of CF on bone without the confounding effects of malabsorption observed in previous CFBD knock-out mice models. Our specific aims are to 1) characterize the skeletal structure of CFBD in vivo: 2) determine the cellular mechanism responsible for skeletal alterations in vitro; and 3) determine at what stage in development CFTR is expressed and synthesized in bone by utilizing in situ hybridization, RT-PCR, and immunohistochemistry. We believe that our research will result in a deeper understanding of the etiology of CFBD and will lead to useful therapeutic interventions.