CF bone disease: Convergence of CFTR and PTH signaling

CF 骨病：CFTR 和 PTH 信号传导的融合

• 批准号: 7898051
• 负责人: GREGORY A CLINES
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898051
• 关键词: Animal Model; Biological Assay; Biology; Bone Density; Bone Diseases; Bone remodeling; Breeding; Calvaria; Cell membrane; Chloride Ion; Chlorides; Chronic; Chronic Disease; Complex; Complication; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Diabetes Mellitus; Disease; Disease Management; Endocytosis; Epidemiology; Fracture; G-Protein-Coupled Receptors; Goals; Hereditary Disease; Hypogonadism; In Vitro; Infection; Intestinal Obstruction; Investigation; Knockout Mice; Kyphosis deformity of spine; Life; Link; Lung; Lung Inflammation; Lung diseases; Malnutrition; Medical; Modeling; Mus; Organ Culture Techniques; Osteoblasts; Osteoclasts; Osteogenesis; Parathyroid Hormone Receptor; Parathyroid Hormone Receptors; Parathyroid Hormones; Patients; Phenotype; Prevalence; Receptor Activation; Research; Risk; Role; Series; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tumor necrosis factor receptor 11b; Vitamin D Deficiency; bone; bone mass; bone turnover; cystic fibrosis patients; disease-causing mutation; high risk; hormone therapy; human PTH protein; improved; in vivo; knockout animal; member; novel; osteoblast differentiation; osteoclastogenesis; pre-clinical; public health relevance; receptor recycling; response; skeletal

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.

描述（由申请人提供）：骨病是最近发现的囊性纤维化（CF）的并发症，CF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疾病。CF骨病导致低骨密度（BMD），并使患者处于脊柱后凸和骨折的高风险。其他众所周知的CF并发症，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CF骨病的病因。然而，流行病学调查和敲除动物模型现在支持骨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，调查骨中CFTR的生物学。CFTR在成骨细胞中表达，靶向CFTR失活可减少体外成骨细胞依赖性新骨形成。氯离子传导和分泌功能缺陷是导致大多数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）信号失调。本探索性提案将探讨CFTR如何调节成骨细胞功能和PTH信号。第一个目的是研究CFTR在成骨细胞和破骨细胞特异性失活小鼠的骨表型。第二个目的是研究CFTR失活是否会破坏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CF骨病的临床前治疗模型中测试甲状旁腺激素的骨合成代谢作用。