title: Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies.
abstract: Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR CAP-Santé (FED 4231), Université Reims Champagne Ardenne, 1, Avenue du Maréchal Juin, 51095, Reims, France. jacky.jacquot@inserm.fr.
authors.forename: J
authors.initials: J
authors.lastname: Jacquot
authors.forename: M
authors.initials: M
authors.lastname: Delion
authors.forename: S
authors.initials: S
authors.lastname: Gangloff
authors.forename: J
authors.initials: J
authors.lastname: Braux
authors.forename: F
authors.initials: F
authors.lastname: Velard
mesh_terms: D016723:Bone Remodeling / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D042241:Early Diagnosis; D006801:Humans; D010024:Osteoporosis / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D010179:Pancreas / Q000378:metabolism
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: Bone disease; CFTR modulators; Cystic fibrosis; F508del-CFTR; Osteoporosis; Treatment