Study summary · research use only
Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This mouse study examined how activation of the receptor GPR54 by its ligand Kisspeptin-10 (Kp-10) affects osteoclasts, cells involved in bone loss. The authors report that Kp-10 binding to Gpr54 caused the phosphatase Dusp18 to dephosphorylate Src at Tyr 416, noting that GPCRs are targets for approximately 35% of approved drugs. Kiss1, Gpr54, and Dusp18 knockout mice showed increased osteoclast activity and bone loss, while Kp-10 treatment reduced osteoclast activity and bone loss in vivo. The authors describe Gpr54 recruiting both Src and Dusp18 at a proline/arginine-rich motif, and suggest Kp-10/Gpr54 signaling as a potential target related to bone resorption via Dusp18-mediated Src dephosphorylation.
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.
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