ePS05.5 Cystic fibrosis bone disease: Is the CFTR corrector C18 an option for therapy?

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.