title: Bone demineralization is improved by ivacaftor in patients with cystic fibrosis carrying the p.Gly551Asp mutation.
abstract: Low bone mineral density (BMD) is a common problem in adults with cystic fibrosis (CF), the etiology of which is multifactorial. In this study, we provide the first evidence that ivacaftor improves BMD in CF patients carrying the p.Gly551Asp mutation. Consistently, in vitro experiments with TNF-α-stimulated primary F508del-CFTR osteoblasts demonstrated that correction of p.Phe508del-CFTR markedly decreased RANKL protein production, a major factor of bone resorption. These clinical and fundamental observations suggest that rescue of mutated CFTR protein improves bone remodeling and support the link between CFTR and bone cell physiology. These findings represent a step forward in the development of potential new therapies for CF-related bone disease.
authors.affiliation: INSERM U1151, Service de Pneumo-Pédiatrie, Hopital Necker, Université Paris Sorbonne, Paris, France. Electronic address: isabelle.sermet@nck.aphp.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sermet-Gaudelus
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, BIOS, Université Reims Champagne Ardenne, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Delion
authors.affiliation: Service de Médecine Interne, Centre Hospitalier Lyon-Sud. Lyon, Université Lyon 1, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durieu
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, BIOS, Université Reims Champagne Ardenne, France.
authors.forename: Jacky
authors.initials: J
authors.lastname: Jacquot
authors.affiliation: Service de Pneumologie, Hôpital Cochin, Université Paris Sorbonne, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hubert
mesh_terms: D000328:Adult; D000627:Aminophenols / Q000008:administration & dosage*; D018488:Bone Demineralization, Pathologic / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D065101:Chloride Channel Agonists / Q000008:administration & dosage; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage*; D013223:Statistics as Topic
chemical_list: D000627:Aminophenols; D065101:Chloride Channel Agonists; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor
keywords: Bone density; CFTR corrector; Cystic fibrosis; RANKL