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 () and Jianru Xiao ()
Additional contact information
Zhenxi Li: University of Shanghai for Science and Technology
Xinghai Yang: Shanghai Changzheng Hospital, Naval Medical University
Ruifeng Fu: University of Shanghai for Science and Technology
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
Tianying Xie: University of Shanghai for Science and Technology
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

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-44852-9

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