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

Zhenxi LiXinghai YangRuifeng FuZhipeng WuShengzhao XuJian JiaoMing QianLong ZhangChunbiao WuTianying XieJiqiang YaoZhixiang WuWenjun LiGuoli MaYu YouYihua ChenHan-Kun ZhangYiyun ChengXiaolong TangPengfei WuGewei LianHaifeng WeiJian ZhaoJianrong XuLianzhong AiStefan SiwkoYue WangJin DingGaojie SongJian LuoMingyao LiuJianru Xiao
Published in: Nature communications (2024)
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.
Keyphrases
  • bone loss
  • tyrosine kinase
  • fatty acid
  • gene expression
  • metabolic syndrome
  • dna methylation
  • type diabetes
  • mouse model
  • bone mineral density