The Effects of CFTR Dysfunction on Bone Formation

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DESCRIPTION (provided by applicant): Median survival for people with Cystic Fibrosis (CF) has increased to >35 years of age. As more CF patients survive well into adulthood poor bone quality has emerged as a challenging burden of this chronic disease. Low bone density and increased fracture rates in CF are well-documented but poorly understood. Although the prevalence for CFBD (Cystic Fibrosis bone disease) is high in adults, it is also present in children. Despite its prevalence, CFBD remains minimally characterized and an understanding of its pathogenesis remains limited. Our major objective is to fully characterize CFBD in a murine model of cystic fibrosis at the structural and cellular level, as it has the potential to provide a deeper understanding of the pathogenesis of CFBD. Murine models of CF are particularly useful for assessing the direct role of CFTR in skeletal homeostasis as these animals do not have severe pulmonary or pancreatic disease. Preliminary data generated demonstrate that from as early as 3 weeks of age through adulthood, these cftr-/- animals have decreased bone mass which is characterized by thinner trabeculae, and thinner cortical bone, as well as, decreased bone volume and strength thus providing a model similar to human disease. We hypothesize that this CF model will manifest a complex bone lesion with low bone density and increased bone fragility similar to that which is observed in CF patients. It is likely that altered CFTR function in a number of bone cell lineages plays a central role in CFBD in humans. However, based on our initial studies we believe the lack of CFTR in the osteoblast is likely to be the primary problem with alterations in osteoclast function a secondary consequence of inflammation. By employing in situ hybridization, RT-PCR, and immunohistochemistry as well as standard patch clamp techniques, the functional role of CFTR in osteoblasts and osteoclasts will be examined. In addition osteoblasts and osteoclasts will be examined in vitro to determine which cell type is responsible for the primary lesion. Lastly we will use a repetitive aerosolized LPS model to determine if chronic inflammation augments the skeletal phenotype of CFBD in the murine model by quantifying bone density and micro-architecture cellular activity using static and dynamic bone histomorphometry and serum markers of bone turnover. By clarifying the exact nature and evolution of the low BMD, and elucidating whether there is a primary defect in bone cell activity, more evidence-based intervention trials can be undertaken to address prevention and management of CFBD. With a stronger, healthier skeleton, the quality of life of patients with CF can be improved.