CF bone disease: Convergence of CFTR and PTH signaling

描述(申请人提供)：骨病是囊性纤维化(CF)的一种新近发现的并发症，这是一种由囊性纤维化跨膜调节因子(CFTR)突变引起的隐性遗传病。Cf骨病导致低骨密度(BMD)，并使患者面临脊柱后凸和骨折的高风险。其他众所周知的CF并发症，如慢性肺部炎症、营养不良、维生素D缺乏和性腺功能减退，都被认为是导致CF骨病的原因。然而，流行病学调查和基因敲除动物模型现在支持骨骼中CFTR失活与低骨密度之间的直接联系。我们进行了一系列的初步研究，研究了CFTR在骨骼中的生物学作用。CFTR在成骨细胞中表达，靶向失活的CFTR在体外减少了成骨细胞依赖的新骨形成。氯离子传导和分泌功能缺陷是大多数CF相关疾病的原因；然而，我们的数据表明，CFTR失活导致的骨形成减少可能源于甲状旁腺激素(PTH)信号的失调。这项探索性的建议将研究CFTR如何调节成骨细胞的功能和甲状旁腺素信号。第一个目的是检测成骨细胞和破骨细胞特异性CFTR失活的小鼠的骨表型。第二个目的是研究CFTR失活是否扰乱成骨细胞下游信号通路的甲状旁腺激素受体激活。最后一个目的是在临床前治疗CF骨病的模型中测试PTH的骨合成代谢作用。 公共卫生相关性：囊性纤维性骨病的影响预计将增加，因为由于肺部疾病管理的改善，囊性纤维化患者的寿命更长。这项探索性的建议将研究CFTR在调控骨形成中的新作用。明确CFTR在骨骼中的作用机制将进一步发展靶向治疗以减少囊性纤维化相关骨折的发生。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.