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Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src

Author

Listed:
  • Zhenxi Li

    (University of Shanghai for Science and Technology
    Shanghai Changzheng Hospital, Naval Medical University
    East China Normal University
    Harvard Medical School)

  • Xinghai Yang

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Ruifeng Fu

    (University of Shanghai for Science and Technology
    Shanghai Changzheng Hospital, Naval Medical University)

  • Zhipeng Wu

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Shengzhao Xu

    (East China Normal University)

  • Jian Jiao

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Ming Qian

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Long Zhang

    (University of Shanghai for Science and Technology)

  • Chunbiao Wu

    (University of Shanghai for Science and Technology
    Shanghai Changzheng Hospital, Naval Medical University)

  • Tianying Xie

    (University of Shanghai for Science and Technology
    Shanghai Changzheng Hospital, Naval Medical University)

  • Jiqiang Yao

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Zhixiang Wu

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Wenjun Li

    (East China Normal University)

  • Guoli Ma

    (East China Normal University)

  • Yu You

    (East China Normal University)

  • Yihua Chen

    (East China Normal University)

  • Han-kun Zhang

    (East China Normal University)

  • Yiyun Cheng

    (East China Normal University)

  • Xiaolong Tang

    (Hunan University)

  • Pengfei Wu

    (Harvard Medical School)

  • Gewei Lian

    (Harvard Medical School)

  • Haifeng Wei

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Jian Zhao

    (Shanghai Changzheng Hospital, Naval Medical University)

  • Jianrong Xu

    (Shanghai University of Traditional Chinese Medicine)

  • Lianzhong Ai

    (University of Shanghai for Science and Technology)

  • Stefan Siwko

    (Texas A&M University Health Science Center)

  • Yue Wang

    (Naval Medical University)

  • Jin Ding

    (Naval Medical University)

  • Gaojie Song

    (East China Normal University)

  • Jian Luo

    (Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine)

  • Mingyao Liu

    (East China Normal University)

  • Jianru Xiao

    (University of Shanghai for Science and Technology
    Shanghai Changzheng Hospital, Naval Medical University
    East China Normal University)

Abstract

Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for ∼35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18. Kiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.

Suggested Citation

  • Zhenxi Li & Xinghai Yang & Ruifeng Fu & Zhipeng Wu & Shengzhao Xu & Jian Jiao & Ming Qian & Long Zhang & Chunbiao Wu & Tianying Xie & Jiqiang Yao & Zhixiang Wu & Wenjun Li & Guoli Ma & Yu You & Yihua , 2024. "Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44852-9
    DOI: 10.1038/s41467-024-44852-9
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    References listed on IDEAS

    as
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