Baud'huin Marc, Lamoureux François, Jacques Camille, Rodriguez Calleja Lidia, Quillard Thibaut, Charrier Céline, Amiaud Jérome, Berreur Martine, Brounais-LeRoyer Bénédicte, Owen Robert, Reilly Gwendolen C, Bradner James E, Heymann Dominique, Ory Benjamin
INSERM, UMR 957, équipe labellisée ligue 2012, 1 Rue Gaston Veil, 44035 Nantes, France; Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, 44035 Nantes, France; Nantes University Hospital, Nantes, France.
INSERM, UMR 957, équipe labellisée ligue 2012, 1 Rue Gaston Veil, 44035 Nantes, France; Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, 44035 Nantes, France.
Bone. 2017 Jan;94:10-21. doi: 10.1016/j.bone.2016.09.020. Epub 2016 Sep 23.
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.
组蛋白修饰对于维持转录程序至关重要。BET蛋白是一类重要的“组蛋白阅读蛋白”，最近被描述为在骨生物学中必不可少。本研究提出了抑制BET蛋白治疗骨质疏松症的机会。我们发现，药理学上的BET蛋白抑制剂JQ1通过增加小梁骨体积和恢复力学性能，挽救了卵巢切除术后骨质疏松模型中的病理性骨丢失。BET蛋白抑制在体外抑制破骨细胞分化和活性以及成骨细胞生成。此外，我们表明，经处理的不具有吸收功能的破骨细胞仍可激活成骨细胞分化。此外，使用RNA干扰特异性抑制BRD4可抑制破骨细胞分化，但强烈激活成骨细胞矿化活性。从机制上讲，JQ1抑制主要破骨细胞转录因子NFATc1和成骨细胞转录因子Runx2的表达。这些发现有力地支持了靶向表观遗传染色质调节因子（如BET蛋白）可能为治疗骨质疏松症等骨相关疾病提供一种有前景的替代方法。
