Cystic Fibrosis and Bone Disease: Defective Osteoblast Maturation with the F508del Mutation in Cystic Fibrosis Transmembrane Conductance Regulator

Velard, Frédéric; Delion, M.; Hénaff, Carole Le; Guillaume, Christine; Gangloff, Sophie C.; Jacquot, Jacky; Tabary, Olivier; Touqui, Lhousseine; Barthes, F. Le Pimpec; Sermet‐Gaudelus, Isabelle

doi:10.1164/rccm.201312-2144le

Cited by 24 publications

(30 citation statements)

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“…The decrease in the percentage of F t /F 0 represents the increase of CFTR chloride conductance. The specific CFTR inhibitor CFTR inh-172 (10 µM for 24 h) was used to verify that the signal observed was CFTR-mediated in healthy osteoblasts (non-CF), as we previously showed [11]. In the presence of CFTR inh-172 , no decrease in fluorescence level was found in healthy osteoblasts+ CFTR inh-172 (data not shown) [11].…”

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confidence: 67%

“…The specific CFTR inhibitor CFTR inh-172 (10 µM for 24 h) was used to verify that the signal observed was CFTR-mediated in healthy osteoblasts (non-CF), as we previously showed [11]. In the presence of CFTR inh-172 , no decrease in fluorescence level was found in healthy osteoblasts+ CFTR inh-172 (data not shown) [11]. The initial iodine influx rate following the addition of each solution was computed from changes in YFP fluorescence using nonlinear regression.…”

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confidence: 96%

“…e) Basal production of COX-2 metabolite PGE 2 assessed by enzyme immunosorbent assay in 24-h supernatants. All experiments were carried out after a 14-day culture-confluent period in healthy and CF osteoblasts (n=4 healthy donors, n=3 CF patients homozygous for the F508del mutation; n=1 CF patient heterozygous for the F508del mutation in CFTR), treated or not with C18 (10 μM for 24 h contribution by which F508del mutation in CFTR resulted in a severe, defective osteoblast maturation arising from an increased RANK ligand (RANKL)/OPG mRNA ratio and a drastic reduction in production of the cyclo-oxygenase (COX)-2 metabolite prostaglandin (PG)E 2 , a key regulator of bone turnover [11]. Another report also showed an elevated RANKL/OPG ratio in the serum of children and adolescents with CF compared with that observed in healthy controls [2].…”

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confidence: 99%

“…We therefore tested the effect of the corrector C18 on CFTR channel activity, the expression level of RANKL/OPG mRNA ratio and COX-2/PGE 2 expression and production in osteoblasts with the F508del mutation. F508del osteoblasts were obtained from trabecular bone explants prepared from rib fragments harvested during lung transplantation, as previously described [11]. Normal osteoblasts, used as controls, were obtained from fresh trabecular bone explants of healthy young adults who underwent trauma surgery.…”

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confidence: 99%

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Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy?

et al. 2014

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Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy?

et al. 2014

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“…The cause of CFBD is thought to be multifactorial including pancreatic insufficiency, diabetes mellitus, pulmonary inflammation/infection, sex hormonal insufficiency, vitamin D and vitamin K insufficiency, calcium malabsorption, malnutrition, delayed puberty, use of exogenous glucocorticoids, physical inactivity and the effect of CFTR dysfunction on bone cell activity ( Fig. 1) [11,14,17,27,28,32,33].…”

Section: Pathogenesis and Importance Of Early Diagnosis Of Cfbdmentioning

confidence: 99%

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

Jacquot

Delion²,

Gangloff³

et al. 2015

Osteoporos Int

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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.

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CFTR deletion affects mouse osteoblasts in a gender‐specific manner

Orlando

Morin

Laffont

et al. 2020

Journal Cellular Physiology

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Advancements in research and care have contributed to increase life expectancy of individuals with cystic fibrosis (CF). With increasing age comes a greater likelihood of developing CF bone disease, a comorbidity characterized by a low bone mass and impaired bone quality, which displays gender differences in severity. However, pathophysiological mechanisms underlying this gender difference have never been thoroughly investigated. We used bone marrow-derived osteoblasts and osteoclasts from Cftr +/+ and Cftr −/− mice to examine whether the impact of CF transmembrane conductance regulator (CFTR) deletion on cellular differentiation and functions differed between genders. To determine whether in vitro findings translated into in vivo observations, we used imaging techniques and three-point bending testing. In vitro studies revealed no osteoclast-autonomous defect but impairment of osteoblast differentiation and functions and aberrant responses to various stimuli in cells isolated from Cftr −/− females only. Compared with wild-type controls, knockout mice exhibited a trabecular osteopenic phenotype that was more pronounced in Cftr −/− males than Cftr −/− females. Bone strength was reduced to a similar extent in knockout mice of both genders. In conclusion, we find a trabecular bone phenotype in Cftr −/− mice that was slightly more pronounced in males than females, which is reminiscent of the situation found in patients. However, at the osteoblast level, the pathophysiological mechanisms underlying this phenotype differ between males and females, which may underlie gender differences in the way bone marrow-derived osteoblasts behave in absence of CFTR.

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Cystic Fibrosis and Bone Disease: Defective Osteoblast Maturation with the F508del Mutation in Cystic Fibrosis Transmembrane Conductance Regulator

Cited by 24 publications

References 15 publications

Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy?

Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy?

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

CFTR deletion affects mouse osteoblasts in a gender‐specific manner

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