論文

査読有り 国際誌
2020年6月20日

Novel gene Merlot inhibits differentiation and promotes apoptosis of osteoclasts.

Bone
  • Tomoyuki Yamakawa
  • ,
  • Nobuaki Okamatsu
  • ,
  • Koji Ishikawa
  • ,
  • Shuichi Kiyohara
  • ,
  • Kazuaki Handa
  • ,
  • Erika Hayashi
  • ,
  • Nobuhiro Sakai
  • ,
  • Akiko Karakawa
  • ,
  • Masahiro Chatani
  • ,
  • Mayumi Tsuji
  • ,
  • Katsunori Inagaki
  • ,
  • Yuji Kiuchi
  • ,
  • Takako Negishi-Koga
  • ,
  • Masamichi Takami

138
開始ページ
115494
終了ページ
115494
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.bone.2020.115494

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.

リンク情報
DOI
https://doi.org/10.1016/j.bone.2020.115494
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32569872

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