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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., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

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. [ABSTRACT FROM AUTHOR]

Low bone mass is commonly seen in patients with cystic fibrosis (CF). We investigated whether the F508del mutation could affect the expression of osteoblast genes (cells that form bone) relative to differentiation [coll type 1, osteocalcin (OC), osteopontin (ON), alkaline phosphatase (ALPL), RUNX2, OSX] and maturation [BMP2, SMAD1/2, osteoprotegerin (OPG), receptor activator of NF-kB ligand (RANKL), cyclooxygenase-2 (COX-2)] in human osteoblasts. F508del osteoblasts were obtained from three patients homozygous for the F508del-CFTR mutation and a patient with the F508del/G542X mutation in CFTR. Normal osteoblasts were obtained from bone explants of healthy young adults who underwent trauma surgery. Compared to healthy osteoblasts, RT-PCR data showed no significant difference in osteoblast gene expression related to differentiation in F508del osteoblasts. By contrast, a severe, defective maturation of F508del osteoblasts was found in bone explants of the four CF patients. F508del osteoblasts exhibited a reduced SMAD2, COX-2 expression and higher RANKL/OPG mRNA ratio. Furthermore, we found that the production of OPG protein and COX-2 metabolite prostaglandin E2 (PGE2), two osteogenic activators, was reduced by F508del osteoblasts. Treatment with the CFTR corrector compound C18 markedly increased the F508del-CFTR chloride activity and ameliorated both the RANKL/OPG mRNA ratio and COX-2/PGE2 production in F508del osteoblasts. From these data, we hypothesize that the corrector C18 might be a good candidate to helpful on bone disease. M.D. is a PhD recipient from MESR, Paris; Vertex provided funding support and research material. [ABSTRACT FROM AUTHOR]