Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis
Autor: | Jérôme Amiaud, Lidia Rodriguez Calleja, Marc Baud'huin, Benjamin Ory, Francois Lamoureux, James E. Bradner, Robert Owen, Thibaut Quillard, Martine Berreur, Camille Jacques, Gwendolen C. Reilly, Céline Charrier, Dominique Heymann, Bénédicte Brounais-LeRoyer |
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Přispěvatelé: | Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe Labellisée LIGUE 2012 [Nantes], Department of Materials Science and Engineering [Sheffield], University of Sheffield [Sheffield], Department of Medical Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Dana-Farber Cancer Institute [Boston], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Camille Jacques is founded by INSERM (Institut National de la Santé et de la Recherche Médicale) and Région Pays de la Loire (grant no. 000381794)., ANR-16-CE14-0012,EPIBONE,Rôle des protéines à bromodomaines dans la physiologie osseuse normale(2016), European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), maurice, sandrine, European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Physiology Endocrinology Diabetes and Metabolism Cellular differentiation Bromodomain Osteoclasts Cell Count Epigenesis Genetic 0302 clinical medicine [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology Osteoblast Epigenetic Nuclear Proteins Cell Differentiation Azepines Organ Size Cell biology Chromatin Biomechanical Phenomena RUNX2 medicine.anatomical_structure [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system 030220 oncology & carcinogenesis Osteoclast Female Signal Transduction musculoskeletal diseases medicine.medical_specialty BRD4 Histology Inhibitor Ovariectomy Biology 03 medical and health sciences Internal medicine medicine Animals Humans Transcription factor Osteoblasts Triazoles Mice Inbred C57BL 030104 developmental biology Endocrinology Osteoporosis [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
Zdroj: | BONE BONE, 2017, 94, pp.10-21. ⟨10.1016/j.bone.2016.09.020⟩ BONE, Elsevier, 2017, 94, pp.10-21. ⟨10.1016/j.bone.2016.09.020⟩ |
ISSN: | 1873-2763 8756-3282 |
DOI: | 10.1016/j.bone.2016.09.020⟩ |
Popis: | International audience; Histone modifications are important for maintaining the transcription program. BET proteins, an important class of " histone reading proteins " , have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis. |
Databáze: | OpenAIRE |
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