Bone disease is a recently recognized complication of cystic fibrosis (CF), a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR). CF bone disease results in low bone mineral density (BMD) and places patients at high risk for kyphosis and fracture. Other well-known complications of CF, chronic lung inflammation, malnutrition, vitamin D deficiency and hypogonadism, have all been proposed to cause CF bone disease. However, epidemiological investigations and knockout animal models now support a direct link between CFTR inactivation in bone and low BMD. We performed a series of preliminary studies investigating the biology of CFTR in bone. CFTR expression was expressed in the osteoblast and targeted CFTR inactivation reduced osteoblast-dependent new bone formation in vitro. Defective chloride conductance and secretory function are responsible for most CF-related diseases;however, our data indicate reduced bone formation from CFTR inactivation may originate from dysregulated parathyroid hormone (PTH) signaling. This exploratory proposal will investigate how CFTR regulates osteoblast function and PTH signaling.
The first aim will examine the bone phenotype of mice with osteoblast and osteoclast-specific inactivation of CFTR.
The second aim will examine whether CFTR inactivation disrupts parathyroid hormone receptor activation of osteoblast downstream signaling pathways. The last aim will test the bone anabolic effects of PTH in a preclinical therapeutic model of CF bone disease.
The impact of cystic fibrosis bone disease is expected to increase as cystic fibrosis patients are living longer due to improved lung disease management. This exploratory proposal will investigate a novel role of CFTR in regulating bone formation. Defining the mechanisms of CFTR in bone will further the development of targeted therapies to reduce cystic fibrosis-related fractures.
| Stalvey, Michael S; Clines, Gregory A (2013) Cystic fibrosis-related bone disease: insights into a growing problem. Curr Opin Endocrinol Diabetes Obes 20:547-52 |
| Stalvey, Michael S; Clines, Katrina L; Havasi, Viktoria et al. (2013) Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease. PLoS One 8:e80098 |
| Clines, Gregory A (2011) Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes 18:339-46 |
