Enhanced F508del-CFTR Channel Activity Ameliorates Bone Pathology in Murine Cystic Fibrosis

• DOI: 10.1016/j.ajpath.2013.12.027
• Publication Date: 2014-02-11T21:31:22Z
• Authors: Carole Le Henaff; Eric Haÿ; Frédéric Velard; Caroline Marty; Olivier Tabary; Pierre J. Marie; Jacky P. Jacquot
• Keywords: Male; 0303 health sciences; 1-Deoxynojirimycin; Osteoblasts; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Bone and Bones; F508del-CFTR; 3. Good health; [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials; Disease Models, Animal; 03 medical and health sciences; Mutation; bone disease; Animals; Mice, Inbred CFTR; miglustat; Enzyme Inhibitors; [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials; F508del mouse; Cells, Cultured

In patients with cystic fibrosis (CF), rib and thoracic vertebral fractures can have adverse effects on lung health because the resulting pain and debilitation can impair airway clearance. The F508del mutation in the CF transmembrane conductance regulator (Cftr) gene induces an osteopenic phenotype in humans and mice. N-butyldeoxynojyrimicin (miglustat), an approved drug for treating type 1 Gaucher disease, was found to normalize CFTR-dependent chloride transport in human F508del CFTR lung cells and in nasal mucosa of F508del CF mice. Herein, we investigated whether targeting F508del-CFTR may rescue the skeletal osteopenic phenotype in murine CF. We found that oral administration of low-dose miglustat (120 mg/kg once a day for 28 days) improved bone mass and microarchitecture in the lumbar spine and femur in F508del mice. The increased bone density was associated with an increased bone formation rate and reduced bone resorption. This effect was associated with increased 17β-estradiol but not with insulin-like growth factor 1 serum levels in miglustat-treated F508del mice. Exposure of primary F508del osteoblasts to miglustat partially restored the deficient CFTR-dependent chloride transport in these bone-forming cells. This study provides evidence that reversal of CFTR-dependent chloride transport in osteoblasts normalizes bone mass and microarchitecture in murine CF. These findings may provide a potential therapeutic strategy to prevent or correct the bone disease in patients with CF.