Nature Communications (Feb 2024)
Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
- 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 Chen,
- Han-kun Zhang,
- Yiyun Cheng,
- Xiaolong Tang,
- Pengfei Wu,
- Gewei Lian,
- Haifeng Wei,
- Jian Zhao,
- Jianrong Xu,
- Lianzhong Ai,
- Stefan Siwko,
- Yue Wang,
- Jin Ding,
- Gaojie Song,
- Jian Luo,
- Mingyao Liu,
- Jianru Xiao
Affiliations
- Zhenxi Li
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- Xinghai Yang
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Ruifeng Fu
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- Zhipeng Wu
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Shengzhao Xu
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Jian Jiao
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Ming Qian
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Long Zhang
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- Chunbiao Wu
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- Tianying Xie
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- Jiqiang Yao
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Zhixiang Wu
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Wenjun Li
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Guoli Ma
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Yu You
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Yihua Chen
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Han-kun Zhang
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Yiyun Cheng
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Xiaolong Tang
- School of Biomedical Sciences, Hunan University
- Pengfei Wu
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School
- Gewei Lian
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School
- Haifeng Wei
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Jian Zhao
- Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University
- Jianrong Xu
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine
- Lianzhong Ai
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- Stefan Siwko
- Department of Translational Medical Sciences, Institute of Biosciences and Technology, Texas A&M University Health Science Center
- Yue Wang
- Shanghai Key Lab of Cell Engineering; Translational Medicine Research Center, Naval Medical University
- Jin Ding
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University
- Gaojie Song
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Jian Luo
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine
- Mingyao Liu
- East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
- Jianru Xiao
- Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology
- DOI
- https://doi.org/10.1038/s41467-024-44852-9
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 17
Abstract
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.
