ECTS Abstracts (2015) 1 P156

Increased NF-[kappa]b and reduced Wnt-[beta]-catenin signalling mediate the altered osteoblast differentiation and function in F508[Delta]-CFTR mice

Carole Le Henaff1, Nadine Tarantino2, Emmanuel Laplantine2, Rafik Mansouri1, Dominique Modrowski1, Mylène Zarka1, Valérie Geoffroy1 & Pierre J Marie1


1UMR-1132 Inserm and Université Paris Diderot, Sorbonne Paris Cité, Paris, France; 2Laboratoire de Signalisation et pathogenèse, Institut Pasteur, Paris, France.


Cystic fibrosis is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). We previously reported that the prevalent human F508Δ-mutation in CFTR results in decreased bone formation and reduced bone mass in mice. However, the molecular mechanisms by which the F508Δ-CFTR mutation affects bone formation were unknown. In this study, we analysed the impact of the F508Δ-CFTR mutation on the osteoblast phenotype in mice, and determined the mechanisms underlying this phenotype. Ex vivo studies showed that the F508Δ-CFTR mutation negatively impacts both the differentiation of bone marrow osteoprogenitor cells into osteoblasts and the function of more mature osteoblasts isolated from F508Δ-CFTR mice compared with wild type mice, demonstrating that the mutation reduces osteoblast differentiation and activity in a cell autonomous manner. Treatment with a CFTR corrector rescued the reduced collagen gene expression in F508Δ-CFTR osteoblasts. Mechanistic analysis revealed that both NF-κB signalling and transcriptional activity are activated in F508Δ-CFTR osteoblasts. Functional studies showed that the activation of NF-κB transcriptional activity in mutant osteoblasts was associated with increased β-catenin phosphorylation and altered expression of Wnt-β-catenin target genes. Importantly, pharmacological inhibition of NF-κB activity or activation of canonical Wnt signalling improved or corrected the reduced osteoblast differentiation and function in F508Δ-CFTR osteogenic cells. Overall, the results reveal that the F508Δ-CFTR mutation impairs osteoblast differentiation and function, in a cell-autonomous manner, as a result of overactive NF-κB and reduced Wnt-β-catenin signalling. Moreover, this study indicates that targeting these signalling pathways can rescue the osteoblast dysfunctions induced by the F508Δ-CFTR CFTR mutation in cystic fibrosis.

Disclosure: The authors declared no competing interests.