Novel gene Merlot inhibits differentiation and promotes apoptosis of osteoclasts
| Autor: | Erika Hayashi, Tomoyuki Yamakawa, Shuichi Kiyohara, Akiko Karakawa, Yuji Kiuchi, Nobuaki Okamatsu, Nobuhiro Sakai, Masamichi Takami, Koji Ishikawa, Takako Negishi-Koga, Katsunori Inagaki, Kazuaki Handa, Mayumi Tsuji, Masahiro Chatani |
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| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Histology Physiology Endocrinology Diabetes and Metabolism T cell Osteoclasts Apoptosis Bone Marrow Cells 030209 endocrinology & metabolism Bone resorption Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Osteoclast medicine Animals Bone Resorption Glycogen synthase Derepression Caspase NFATC Transcription Factors biology Chemistry RANK Ligand Cell Differentiation Cell biology 030104 developmental biology medicine.anatomical_structure biology.protein Signal Transduction |
| Zdroj: | Bone. 138:115494 |
| ISSN: | 8756-3282 |
| DOI: | 10.1016/j.bone.2020.115494 |
| Popis: | Extended osteoclast longevity is deeply involved in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis, though the mechanisms that determine osteoclast lifespan are not fully understood. Here we present findings indicating that the newly characterized gene Merlot, which encodes a highly conserved yet uncharacterized protein in vertebrates, is an important regulator for termination of osteoclastogenesis via induction of apoptosis. Mice lacking Merlot exhibited low bone mass due to increased osteoclast and bone resorption. Furthermore, osteoclast precursors overexpressing Merlot failed to differentiate into mature osteoclasts, while Merlot deficiency led to hyper-nucleation and prolonged survival of osteoclasts, accompanied by sustained nuclear localization of nuclear factor of activated T cell c1 (NFATc1) and derepression of glycogen synthase kinase-3β (GSK3β) activity, known to regulate NFATc1 activity and induce apoptosis. Merlot-deficient osteoclasts were found to represent suppression of caspase-3-mediated apoptosis and Merlot deficiency caused transcriptional downregulation of a proapoptotic cascade, including Bax, Bak, Noxa, and Bim, as well as the executor caspase members Casp-3, -6, and -7, and upregulation of anti-apoptotic Bcl2, resulting in a low apoptotic threshold. Thus, Merlot regulates osteoclast lifespan by inhibition of differentiation and simultaneous induction of apoptosis via regulation of the NFATc1-GSK3β axis. |
| Databáze: | OpenAIRE |
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