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TMCO1-mediated Ca2+ leak underlies osteoblast functions via CaMKII signaling

Author

Listed:
  • Jianwei Li

    (China Astronaut Research and Training Center
    The Fourth Military Medical University)

  • Caizhi Liu

    (China Astronaut Research and Training Center)

  • Yuheng Li

    (China Astronaut Research and Training Center)

  • Qiaoxia Zheng

    (Peking University)

  • Youjia Xu

    (The Second Affiliated Hospital of Soochow University)

  • Beibei Liu

    (Peking University)

  • Weijia Sun

    (China Astronaut Research and Training Center)

  • Yuan Li

    (The Second Affiliated Hospital of Soochow University)

  • Shuhui Ji

    (Beijing Proteome Research Center, Beijing Institute of Radiation Medicine)

  • Mingwei Liu

    (Beijing Proteome Research Center, Beijing Institute of Radiation Medicine)

  • Jing Zhang

    (Tsinghua University)

  • Dingsheng Zhao

    (China Astronaut Research and Training Center)

  • Ruikai Du

    (China Astronaut Research and Training Center)

  • Zizhong Liu

    (China Astronaut Research and Training Center)

  • Guohui Zhong

    (China Astronaut Research and Training Center)

  • Cuiwei Sun

    (Peking University)

  • Yanqing Wang

    (China Astronaut Research and Training Center)

  • Jinping Song

    (China Astronaut Research and Training Center)

  • Shu Zhang

    (The Fourth Military Medical University)

  • Jun Qin

    (Beijing Proteome Research Center, Beijing Institute of Radiation Medicine)

  • Shukuan Ling

    (China Astronaut Research and Training Center)

  • Xianhua Wang

    (Peking University)

  • Yingxian Li

    (China Astronaut Research and Training Center)

Abstract

Transmembrane and coiled-coil domains 1 (TMCO1) is a recently identified Ca2+ leak channel in the endoplasmic reticulum. TMCO1 dysfunction in humans is associated with dysmorphism, mental retardation, glaucoma and the occurrence of cancer. Here we show an essential role of TMCO1 in osteogenesis mediated by local Ca2+/CaMKII signaling in osteoblasts. TMCO1 levels were significantly decreased in bone from both osteoporosis patients and bone-loss mouse models. Tmco1−/− mice exhibited loss of bone mass and altered microarchitecture characteristic of osteoporosis. In the absence of TMCO1, decreased HDAC4 phosphorylation resulted in nuclear enrichment of HADC4, which leads to deacetylation and degradation of RUNX2, the master regulator of osteogenesis. We further demonstrate that TMCO1-mediated Ca2+ leak provides local Ca2+ signals to activate the CaMKII-HDAC4-RUNX2 signaling axis. The establishment of TMCO1 as a pivotal player in osteogenesis uncovers a novel potential therapeutic target for ameliorating osteoporosis.

Suggested Citation

  • Jianwei Li & Caizhi Liu & Yuheng Li & Qiaoxia Zheng & Youjia Xu & Beibei Liu & Weijia Sun & Yuan Li & Shuhui Ji & Mingwei Liu & Jing Zhang & Dingsheng Zhao & Ruikai Du & Zizhong Liu & Guohui Zhong & C, 2019. "TMCO1-mediated Ca2+ leak underlies osteoblast functions via CaMKII signaling," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09653-5
    DOI: 10.1038/s41467-019-09653-5
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    Cited by:

    1. Weijia Sun & Shuai Guo & Yuheng Li & JianWei Li & Caizhi Liu & Yafei Chen & Xuzhao Wang & Yingjun Tan & Hua Tian & Cheng Wang & Ruikai Du & Guohui Zhong & Sai Shi & Biao Ma & Chang Qu & Jingxuan Fu & , 2022. "Anoctamin 1 controls bone resorption by coupling Cl− channel activation with RANKL-RANK signaling transduction," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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