title: Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis.
abstract: Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti-osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at low levels. Genetic studies showed that Krt8 deletion (Krt8(-/-)) in F508del-Cftr mice increased the levels of circulating markers of bone formation, corrected the expression of osteoblast phenotypic genes, promoted trabecular bone formation and improved bone mass and microarchitecture. Mechanistically, Krt8 deletion in F508del-Cftr mice corrected overactive NF-κB signaling and decreased Wnt-β-catenin signaling induced by the F508del-Cftr mutation in osteoblasts. In vitro, treatment with compound 407, which specifically disrupts the Krt8-F508del-Cftr interaction in epithelial cells, corrected the abnormal NF-κB and Wnt-β-catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt-β-catenin signaling and bone formation in F508del-Cftr mice. Collectively, the results show that genetic or pharmacologic targeting of Krt8 leads to correction of osteoblast dysfunctions, altered bone formation and osteopenia in F508del-Cftr mice, providing a therapeutic strategy targeting the Krt8-F508del-CFTR interaction to correct the abnormal bone formation and bone loss in cystic fibrosis.
authors.affiliation: INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Le Henaff
authors.affiliation: INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Faria Da Cunha
authors.affiliation: INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hatton
authors.affiliation: INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Tondelier
authors.affiliation: INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.affiliation: INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Collet
authors.affiliation: INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Zarka
authors.affiliation: INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Geoffroy
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria and.
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.affiliation: Laboratoire de Signalisation et Pathogenèse, Institut Pasteur, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Laplantine
authors.affiliation: INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Edelman
authors.affiliation: INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sermet-Gaudelus
authors.affiliation: INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France, pierre.marie@inserm.fr.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology* / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006801:Humans; D053533:Keratin-8 / Q000235:genetics*; D008297:Male; D051379:Mice; D016328:NF-kappa B; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D015398:Signal Transduction; D055815:Young Adult; D051176:beta Catenin
chemical_list: D053533:Keratin-8; D016328:NF-kappa B; D051176:beta Catenin