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Dramatic Elevation of Plasma Metastin Concentrations in Human Pregnancy: Metastin as a Novel Placenta-Derived Hormone in Humans

Discovery Research Laboratories I, Pharmaceutical Division, Takeda Chemical Industries Ltd. (Y.H., H.M., Y.T., T.O., C.K., M.F.), Wadai, Tsukuba, Ibaraki 300-4293, Japan; and Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba (S.U.), Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Address all correspondence and requests for reprints to: Hirokazu Matsumoto, Ph.D., Discovery Research Laboratories I, Pharmaceutical Division, Takeda Chemical Industries Ltd., Wadai-10, Tsukuba, Ibaraki 300-4293, Japan. E-mail: matsumoto_hirokazu{at}takeda.co.jp.

Metastin is a novel peptide that was recently isolated from human placenta as the endogenous ligand of an orphan heptahelical receptor, hOT7T175. Metastin has been shown to suppress the motility of hOT7T175-transfected melanoma cells; however, studies of the physiological function of metastin have begun only recently. To investigate the possibility that metastin is an endocrine peptide, we determined the immunoreactive (ir-) metastin concentration in human plasma using our newly developed, sensitive, and specific two-site enzyme immunoassay. The plasma concentrations of ir-metastin in males and females were 1.30 ± 0.14 (n = 12) and 1.31 ± 0.37 fmol/ml (n = 10), respectively. As metastin is known to be abundant in human placenta, the ir-metastin concentration in the maternal plasma was then determined. The ir-metastin concentrations were 1230 ± 346 fmol/ml (n = 11) in the first trimester, 4590 ± 555 (n = 16) in the second trimester, and 9590 ± 1640 (n = 12) in the third trimester. On d 5 after delivery, the ir-metastin concentration returned to nearly the nonpregnant level (7.63 ± 1.33 fmol/ml; n = 10), suggesting that ir-metastin increases in pregnancy and is derived mainly from the placenta. The plasma from both nonpregnant and pregnant women showed a single ir-metastin peak at the same retention time as authentic metastin on reverse phase HPLC analysis, indicating that the major portion of the circulating metastin, as determined by our two-site enzyme immunoassay, represents endogenous metastin. Histochemical studies of human placenta localized metastin mRNA and immunoreactivity to the syncytiotrophoblasts. The present study provides evidence for metastin as a novel placenta-derived hormone in humans.

Abbreviations: CHO, Chinese hamster ovary; E2, estradiol; EIA, enzyme immunoassay; hCG, human chorionic gonadotropin; hPL, human placental lactogen; HRP, horseradish peroxidase; ir-, immunoreactive; RF, arginine-phenylalanine; RP-HPLC, reverse phase HPLC; SSC, standard saline citrate; TFA, trifluoroacetic acid.

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