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.