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Publication Abstract from PubMed

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 approximately 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.

Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.,Li Z, Yang X, Fu R, Wu Z, Xu S, Jiao J, Qian M, Zhang L, Wu C, Xie T, Yao J, Wu Z, Li W, Ma G, You Y, Chen Y, Zhang HK, Cheng Y, Tang X, Wu P, Lian G, Wei H, Zhao J, Xu J, Ai L, Siwko S, Wang Y, Ding J, Song G, Luo J, Liu M, Xiao J Nat Commun. 2024 Feb 12;15(1):1300. doi: 10.1038/s41467-024-44852-9. PMID:38346942^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.