| First Author | Le Henaff C | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 29 | Pages | 18009-17 |
| PubMed ID | 26060255 | Mgi Jnum | J:223758 |
| Mgi Id | MGI:5660162 | Doi | 10.1074/jbc.M115.646208 |
| Citation | Le Henaff C, et al. (2015) Increased NF-kappaB Activity and Decreased Wnt/beta-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in DeltaF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice. J Biol Chem 290(29):18009-17 |
| abstractText | The prevalent human DeltaF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with reduced bone formation and bone loss in mice. The molecular mechanisms by which the DeltaF508-CFTR mutation causes alterations in bone formation are poorly known. In this study, we analyzed the osteoblast phenotype in DeltaF508-CFTR mice and characterized the signaling mechanisms underlying this phenotype. Ex vivo studies showed that the DeltaF508-CFTR mutation negatively impacted the differentiation of bone marrow stromal cells into osteoblasts and the activity of osteoblasts, demonstrating that the DeltaF508-CFTR mutation alters both osteoblast differentiation and function. Treatment with a CFTR corrector rescued the abnormal collagen gene expression in DeltaF508-CFTR osteoblasts. Mechanistic analysis revealed that NF-kappaB signaling and transcriptional activity were increased in mutant osteoblasts. Functional studies showed that the activation of NF-kappaB transcriptional activity in mutant osteoblasts resulted in increased beta-catenin phosphorylation, reduced osteoblast beta-catenin expression, and altered expression of Wnt/beta-catenin target genes. Pharmacological inhibition of NF-kappaB activity or activation of canonical Wnt signaling rescued Wnt target gene expression and corrected osteoblast differentiation and function in bone marrow stromal cells and osteoblasts from DeltaF508-CFTR mice. Overall, the results show that the DeltaF508-CFTR mutation impairs osteoblast differentiation and function as a result of overactive NF-kappaB and reduced Wnt/beta-catenin signaling. Moreover, the data indicate that pharmacological inhibition of NF-kappaB or activation of Wnt/beta-catenin signaling can rescue the abnormal osteoblast differentiation and function induced by the prevalent DeltaF508-CFTR mutation, suggesting novel therapeutic strategies to correct the osteoblast dysfunctions in cystic fibrosis. |
