骨吸收细胞中 Kisspeptin-10 与 Gpr54 的结合通过激活 Dusp18 介导的 Src 去磷酸化来防止骨质流失。
Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.
机构信息
Institute of Orthopedic Biomedical and Device Innovation, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
Institute of Orthopedics, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
出版信息
Nat Commun. 2024 Feb 12;15(1):1300. doi: 10.1038/s41467-024-44852-9.
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.
破骨细胞在衰老过程中过度激活，导致骨质流失。小鼠中 Src 的缺失导致严重的骨质硬化症，这是由于破骨细胞的功能缺陷，表明 Src 功能在破骨细胞中是必不可少的。G 蛋白偶联受体（GPCRs）是约 35%已批准药物的靶点，但目前尚不清楚 GPCRs 如何调节 Src 激酶活性。在这里，我们揭示了 GPR54 被其天然配体 Kisspeptin-10（Kp-10）激活后，导致 Dusp18 将 Src 上的 Tyr 416 去磷酸化。从机制上讲，Gpr54 在其 C 端富含脯氨酸/精氨酸的基序处募集活性 Src 和 Dusp18 磷酸酶。我们表明，Kp-10 与 Gpr54 的结合导致 Dusp18 的上调。Kiss1、Gpr54 和 Dusp18 敲除小鼠均表现出破骨细胞过度激活和骨质流失，而 Kp-10 通过抑制体内破骨细胞活性来阻止骨质流失。因此，Kp-10/Gpr54 是一种很有前途的治疗靶点，可通过 Dusp18 介导的 Src 去磷酸化来抑制骨吸收。
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