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Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis.
Le Henaff, Carole; Faria Da Cunha, Mélanie; Hatton, Aurélie; Tondelier, Danielle; Marty, Caroline; Collet, Corinne; Zarka, Mylène; Geoffroy, Valérie; Zatloukal, Kurt; Laplantine, Emmanuel; Edelman, Aleksander; Sermet-Gaudelus, Isabelle; Marie, Pierre J.
Afiliação
  • Le Henaff C; INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • Faria Da Cunha M; INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
  • Hatton A; INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
  • Tondelier D; INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
  • Marty C; INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • Collet C; INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • Zarka M; INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • Geoffroy V; INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • Zatloukal K; Institute of Pathology, Medical University of Graz, Graz, Austria and.
  • Laplantine E; Laboratoire de Signalisation et Pathogenèse, Institut Pasteur, Paris, France.
  • Edelman A; INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
  • Sermet-Gaudelus I; INSERM U-1151, Team 2, University Paris Descartes, Paris, France.
  • Marie PJ; INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France, pierre.marie@inserm.fr.
Hum Mol Genet ; 25(7): 1281-93, 2016 Apr 01.
Article em En | MEDLINE | ID: mdl-26769674
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-ß-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-ß-catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt-ß-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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteogênese / Doenças Ósseas Metabólicas / Deleção de Genes / Fibrose Cística / Queratina-8 Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Osteogênese / Doenças Ósseas Metabólicas / Deleção de Genes / Fibrose Cística / Queratina-8 Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article