Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
Year: 2024
Type: article
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.
Source: Nature Communications
Authors: 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
Institutions: Beth Israel Deaconess Medical Center, Harvard University, University of Shanghai for Science and Technology, Second Military Medical University, Shanghai Changzheng Hospital, East China Normal University, Hunan University, Shanghai University of Traditional Chinese Medicine, Texas A&M University, Tongji University, Shanghai Sunshine Rehabilitation Center
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G2328948395, G5021667128
OpenAlex ID: W4391756293