IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-44852-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-44852-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-44852-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Wenqing Xu & Stephen C. Harrison & Michael J. Eck, 1997. "Three-dimensional structure of the tyrosine kinase c-Src," Nature, Nature, vol. 385(6617), pages 595-602, February.
    2. Tetsuya Ohtaki & Yasushi Shintani & Susumu Honda & Hirokazu Matsumoto & Akira Hori & Kimiko Kanehashi & Yasuko Terao & Satoshi Kumano & Yoshihiro Takatsu & Yasushi Masuda & Yoshihiro Ishibashi & Takuy, 2001. "Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor," Nature, Nature, vol. 411(6837), pages 613-617, May.
    3. Candice B. Herber & William C. Krause & Liping Wang & James R. Bayrer & Alfred Li & Matthew Schmitz & Aaron Fields & Breanna Ford & Zhi Zhang & Michelle S. Reid & Daniel K. Nomura & Robert A. Nissenso, 2019. "Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    4. William J. Boyle & W. Scott Simonet & David L. Lacey, 2003. "Osteoclast differentiation and activation," Nature, Nature, vol. 423(6937), pages 337-342, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Lavinia Paternoster & Mattias Lorentzon & Liesbeth Vandenput & Magnus K Karlsson & Östen Ljunggren & Andreas Kindmark & Dan Mellstrom & John P Kemp & Caroline E Jarett & Jeff M P Holly & Adrian Sayers, 2010. "Genome-Wide Association Meta-Analysis of Cortical Bone Mineral Density Unravels Allelic Heterogeneity at the RANKL Locus and Potential Pleiotropic Effects on Bone," PLOS Genetics, Public Library of Science, vol. 6(11), pages 1-12, November.
    2. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    3. Yasuaki Uehara & Yusuke Tanaka & Shuyang Zhao & Nikolaos M. Nikolaidis & Lori B. Pitstick & Huixing Wu & Jane J. Yu & Erik Zhang & Yoshihiro Hasegawa & John G. Noel & Jason C. Gardner & Elizabeth J. K, 2023. "Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Nidhi Rohatgi & Wei Zou & Yongjia Li & Kevin Cho & Patrick L. Collins & Eric Tycksen & Gaurav Pandey & Carl J. DeSelm & Gary J. Patti & Anwesha Dey & Steven L. Teitelbaum, 2023. "BAP1 promotes osteoclast function by metabolic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Sichun Yang & Benoît Roux, 2008. "Src Kinase Conformational Activation: Thermodynamics, Pathways, and Mechanisms," PLOS Computational Biology, Public Library of Science, vol. 4(3), pages 1-14, March.
    6. Tom W. Andrew & Lauren S. Koepke & Yuting Wang & Michael Lopez & Holly Steininger & Danielle Struck & Tatiana Boyko & Thomas H. Ambrosi & Xinming Tong & Yuxi Sun & Gunsagar S. Gulati & Matthew P. Murp, 2022. "Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Xiaming Du & Chao Zhang & Xiangqi Zhang & Zhen Qi & Sulin Cheng & Shenglong Le, 2021. "The Impact of Nordic Walking on Bone Properties in Postmenopausal Women with Pre-Diabetes and Non-Alcohol Fatty Liver Disease," IJERPH, MDPI, vol. 18(14), pages 1-10, July.
    8. Hipólito Nicolás Cuesta-Hernández & Julia Contreras & Pablo Soriano-Maldonado & Jana Sánchez-Wandelmer & Wayland Yeung & Ana Martín-Hurtado & Inés G. Muñoz & Natarajan Kannan & Marta Llimargas & Javie, 2023. "An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    9. Nicole Dölker & Maria W Górna & Ludovico Sutto & Antonio S Torralba & Giulio Superti-Furga & Francesco L Gervasio, 2014. "The SH2 Domain Regulates c-Abl Kinase Activation by a Cyclin-Like Mechanism and Remodulation of the Hinge Motion," PLOS Computational Biology, Public Library of Science, vol. 10(10), pages 1-12, October.
    10. Jiahui Du & Yili Liu & Jinrui Sun & Enhui Yao & Jingyi Xu & Xiaolin Wu & Ling Xu & Mingliang Zhou & Guangzheng Yang & Xinquan Jiang, 2024. "ARID1A safeguards the canalization of the cell fate decision during osteoclastogenesis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    11. M. Gabriele Bixel & Kishor K. Sivaraj & Melanie Timmen & Vishal Mohanakrishnan & Anusha Aravamudhan & Susanne Adams & Bong-Ihn Koh & Hyun-Woo Jeong & Kai Kruse & Richard Stange & Ralf H. Adams, 2024. "Angiogenesis is uncoupled from osteogenesis during calvarial bone regeneration," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    12. Atsushi Imai & Rie Yamada & Keigo Yasuda, 2020. "WDR11 Mutations as A Potential Player of Idiopathic Hypogonadotropic Hypogonadism," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 28(3), pages 21661-21665, June.
    13. Wenjing Jin & Xianfeng Lin & Haihua Pan & Chenchen Zhao & Pengcheng Qiu & Ruibo Zhao & Zihe Hu & Yanyan Zhou & Haiyan Wu & Xiao Chen & Hongwei Ouyang & Zhijian Xie & Ruikang Tang, 2021. "Engineered osteoclasts as living treatment materials for heterotopic ossification therapy," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    14. Wenquan Liang & Ru Feng & Xiaojia Li & Xingwei Duan & Shourui Feng & Jun Chen & Yicheng Li & Junqi Chen & Zezheng Liu & Xiaogang Wang & Guangfeng Ruan & Su’an Tang & Changhai Ding & Bin Huang & Zhipen, 2024. "A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44852-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.