title: Overexpression of RANKL in osteoblasts: a possible mechanism of susceptibility to bone disease in cystic fibrosis.
abstract: Bone fragility and loss are a significant cause of morbidity in patients with cystic fibrosis (CF), and the lack of effective therapeutic options means that treatment is more often palliative rather than curative. A deeper understanding of the pathogenesis of CF-related bone disease (CFBD) is necessary to develop new therapies. Defective CF transmembrane conductance regulator (CFTR) protein and chronic inflammation in bone are important components of the CFBD development. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) drive the regulation of bone turnover. To investigate their roles in CFBD, we evaluated the involvement of defective CFTR in their production level in CF primary human osteoblasts with and without inflammatory stimulation, in the presence or not of pharmacological correctors of the CFTR. No major difference in cell ultrastructure was noted between cultured CF and non-CF osteoblasts, but a delayed bone matrix mineralization was observed in CF osteoblasts. Strikingly, resting CF osteoblasts exhibited strong production of RANKL protein, which was highly localized at the cell membrane and was enhanced in TNF (TNF-α) or IL-17-stimulated conditions. Under TNF stimulation, a defective response in OPG production was observed in CF osteoblasts in contrast to the elevated OPG production of non-CF osteoblasts, leading to an elevated RANKL-to-OPG protein ratio in CF osteoblasts. Pharmacological inhibition of CFTR chloride channel conductance in non-CF osteoblasts replicated both the decreased OPG production and the enhanced RANKL-to-OPG ratio. Interestingly, using CFTR correctors such as C18, we significantly reduced the production of RANKL by CF osteoblasts, in both resting and TNF-stimulated conditions. In conclusion, the overexpression of RANKL and high membranous RANKL localization in osteoblasts are related to defective CFTR, and may worsen bone resorption, leading to bone loss in patients with CF. Targeting osteoblasts with CFTR correctors may represent an effective strategy to treat CFBD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Delion
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Braux
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Jourdain
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Guillaume
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Bour
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gangloff
authors.affiliation: Département de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 20-40 Rue Leblanc, Paris, France.
authors.forename: Françoise Le
authors.initials: FL
authors.lastname: Pimpec-Barthes
authors.affiliation: Unité de Pneumo-Pédiatrie Allergologie, Hôpital Necker, Inserm U1551, Université Paris Sorbonne, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sermet-Gaudelus
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Jacky
authors.initials: J
authors.lastname: Jacquot
authors.affiliation: EA 4691, Biomatériaux et Inflammation en Site Osseux, SFR CAP-Santé (FED 4231), Université Reims Champagne-Ardenne, 1 Avenue du Maréchal Juin, Reims, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Velard
mesh_terms: D000293:Adolescent; D000328:Adult; D001847:Bone Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004198:Disease Susceptibility; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult
chemical_list: D020381:Interleukin-17; D053244:Osteoprotegerin; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR correctors; F508del-CFTR; OPG; RANKL; bone disease; cystic fibrosis; osteoblasts