Advertisement

New Insights into Biological Roles of Relaxin and Relaxin-related Peptides

  • Jae-Il Park
  • Chia Lin Chang
  • Sheau Yu Teddy HsuEmail author
Article

Keywords

Public Health Peptide Internal Medicine Biological Role Relaxin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Hisaw FL. Experimental relaxation of the pubic ligment of the guinea pig. Proc Soc Exp Bio Med. 1926;23:661–663.Google Scholar
  2. 2.
    Guico-Lamm ML, Voss EW, Jr., Sherwood OD. Monoclonal antibodies specific for rat relaxin. I. Production and characterization of monoclonal antibodies that neutralize rat relaxin's bioactivity in vivo. Endocrinology. 1988;123:2472–2478.Google Scholar
  3. 3.
    Hwang JJ, Lee AB, Fields PA, Haab LM, Mojonnier LE, Sherwood OD. Monoclonal antibodies specific for rat relaxin. V. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts development of the mammary apparatus and, hence, lactational performance in rats. Endocrinology. 1991;129:3034–3042.PubMedGoogle Scholar
  4. 4.
    Zhao S, Malmgren CH, Shanks RD, Sherwood OD. Monoclonal antibodies specific for rat relaxin. VIII. Passive immunization with monoclonal antibodies throughout the second half of pregnancy reduces water consumption in rats. Endocrinology. 1995;136:1892–1897.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhao S, Kuenzi MJ, Sherwood OD. Monoclonal antibodies specific for rat relaxin. IX. Evidence that endogenous relaxin promotes growth of the vagina during the second half of pregnancy in rats. Endocrinology. 1996;137:425–430.PubMedCrossRefGoogle Scholar
  6. 6.
    Guico-Lamm ML, Sherwood OD. Monoclonal antibodies specific for rat relaxin. II. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts birth in intact rats. Endocrinology. 1988;123:2479–2485.PubMedGoogle Scholar
  7. 7.
    Hwang JJ, Sherwood OD. Monoclonal antibodies specific for rat relaxin. III. Passive immunization with monoclonal antibodies throughout the second half of pregnancy reduces cervical growth and extensibility in intact rats. Endocrinology. 1988;123:2486–2490.PubMedGoogle Scholar
  8. 8.
    Hwang JJ, Shanks RD, Sherwood OD. Monoclonal antibodies specific for rat relaxin. IV. Passive immunization with monoclonal antibodies during the antepartum period reduces cervical growth and extensibility, disrupts birth, and reduces pup survival in intact rats. Endocrinology. 1989;125:260–266.PubMedGoogle Scholar
  9. 9.
    Kuenzi MJ, Sherwood OD. Monoclonal antibodies specific for rat relaxin. VII. Passive immunization with monoclonal antibodies throughout the second half of pregnancy prevents development of normal mammary nipple morphology and function in rats. Endocrinology. 1992;131:1841–1847.CrossRefPubMedGoogle Scholar
  10. 10.
    Lee AB, Hwang JJ, Haab LM, Fields PA, Sherwood OD. Monoclonal antibodies specific for rat relaxin. VI. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts histological changes associated with cervical softening at parturition in rats. Endocrinology. 1992;130:2386–2391.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhao S, Sherwood OD. Monoclonal antibodies specific for rat relaxin. X. Endogenous relaxin induces changes in the histological characteristics of the rat vagina during the second half of pregnancy. Endocrinology. 1998;139:4726–4734.CrossRefPubMedGoogle Scholar
  12. 12.
    Mushayandebvu TI, Rajabi MR. Relaxin stimulates interstitial collagenase activity in cultured uterine cervical cells from nonpregnant and pregnant but not immature guinea pigs; estradiol-17 beta restores relaxin's effect in immature cervical cells. Biol Reprod. 1995;53:1030–1037.CrossRefPubMedGoogle Scholar
  13. 13.
    Lenhart JA, Ryan PL, Ohleth KM, Palmer SS, Bagnell CA. Relaxin increases secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 during uterine and cervical growth and remodeling in the pig. Endocrinology. 2001;142:3941–3949.CrossRefPubMedGoogle Scholar
  14. 14.
    Palejwala S, Stein DE, Weiss G, Monia BP, Tortoriello D, Goldsmith LT. Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway. Endocrinology. 2001;142:3405–3413.CrossRefPubMedGoogle Scholar
  15. 15.
    Hwang JJ, Macinga D, Rorke EA. Relaxin modulates human cervical stromal cell activity. J Clin Endocrinol Metab. 1996;81:3379–3384.CrossRefPubMedGoogle Scholar
  16. 16.
    Hudson P, Haley J, John M, Cronk M, Crawford R, Haralambidis J, Tregear G, Shine J, Niall H. Structure of a genomic clone encoding biologically active human relaxin. Nature. 1983;301:628–631.CrossRefPubMedGoogle Scholar
  17. 17.
    Hudson P, John M, Crawford R, Haralambidis J, Scanlon D, Gorman J, Tregear G, Shine J, Niall H. Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of cDNA clones. Embo J. 1984;3:2333–2339.PubMedGoogle Scholar
  18. 18.
    Adham IM, Burkhardt E, Benahmed M, Engel W. Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells. J Biol Chem. 1993;268:26668–26672.PubMedGoogle Scholar
  19. 19.
    Chassin D, Laurent A, Janneau JL, Berger R, Bellet D. Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta. Genomics. 1995;29:465–470.PubMedCrossRefGoogle Scholar
  20. 20.
    Conklin D, Lofton-Day CE, Haldeman BA, Ching A, Whitmore TE, Lok S, Jaspers S. Identification of INSL5, a new member of the insulin superfamily. Genomics. 1999;60:50–56.CrossRefPubMedGoogle Scholar
  21. 21.
    Lok S, Johnston DS, Conklin D, Lofton-Day CE, Adams RL, Jelmberg AC, Whitmore TE, Schrader S, Griswold MD, Jaspers SR. Identification of INSL6, a new member of the insulin family that is expressed in the testis of the human and rat. Biol Reprod. 2000;62:1593–1599.CrossRefPubMedGoogle Scholar
  22. 22.
    Bathgate RA, Samuel CS, Burazin TC, Layfield S, Claasz AA, Reytomas IG, Dawson NF, Zhao C, Bond C, Summers RJ, Parry LJ, Wade JD, Tregear GW. Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J Biol Chem. 2002;277:1148–1157.CrossRefPubMedGoogle Scholar
  23. 23.
    Sherwood OD. Relaxin's physiological roles and other diverse actions. Endocr Rev. 2004;25:205–234.CrossRefPubMedGoogle Scholar
  24. 24.
    Hansell DJ, Bryant-Greenwood GD, Greenwood FC. Expression of the human relaxin H1 gene in the decidua, trophoblast, and prostate. J Clin Endocrinol Metab. 1991;72:899–904.PubMedGoogle Scholar
  25. 25.
    Gunnersen JM, Crawford RJ, Tregear GW. Expression of the relaxin gene in rat tissues. Mol Cell Endocrinol. 1995;110:55–64.CrossRefPubMedGoogle Scholar
  26. 26.
    Bullesbach EE, Yang S, Schwabe C. The receptor-binding site of human relaxin II. A dual prong-binding mechanism. J Biol Chem. 1992;267:22957–22960.PubMedGoogle Scholar
  27. 27.
    Bullesbach EE, Schwabe C. The relaxin receptor-binding site geometry suggests a novel gripping mode of interaction. J Biol Chem. 2000;275:35276–35280.CrossRefPubMedGoogle Scholar
  28. 28.
    Eigenbrot C, Randal M, Quan C, Burnier J, O'Connell L, Rinderknecht E, Kossiakoff AA. X-ray structure of human relaxin at 1.5 A. Comparison to insulin and implications for receptor binding determinants. J Mol Biol. 1991;221:15–21.PubMedGoogle Scholar
  29. 29.
    Bullesbach EE, Schwabe C. The trap-like relaxin-binding site of the leucine-rich G-protein-coupled receptor 7. J Biol Chem. 2005;280:14051–14056.PubMedCrossRefGoogle Scholar
  30. 30.
    Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ. Activation of orphan receptors by the hormone relaxin. Science. 2002;295:671–674.CrossRefPubMedGoogle Scholar
  31. 31.
    Parsell DA, Mak JY, Amento EP, Unemori EN. Relaxin binds to and elicits a response from cells of the human monocytic cell line, THP-1. J Biol Chem. 1996;271:27936–27941.PubMedCrossRefGoogle Scholar
  32. 32.
    Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, van Duin M, Hsueh AJ. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol. 2000;14:1257–1271.PubMedCrossRefGoogle Scholar
  33. 33.
    Zhao L, Roche PJ, Gunnersen JM, Hammond VE, Tregear GW, Wintour EM, Beck F. Mice without a Functional Relaxin Gene Are Unable to Deliver Milk to Their Pups. Endocrinology. 1999;140:445–453.PubMedCrossRefGoogle Scholar
  34. 34.
    Krajnc-Franken MA, van Disseldorp AJ, Koenders JE, Mosselman S, van Duin M, Gossen JA. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol. 2004;24:687–696.CrossRefPubMedGoogle Scholar
  35. 35.
    Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate RA, Hsueh AJ. H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. J Biol Chem. 2003;278:7855–7862.CrossRefPubMedGoogle Scholar
  36. 36.
    Nef S, Parada LF. Cryptorchidism in mice mutant for Insl3. Nat Genet. 1999;22:295–299.PubMedCrossRefGoogle Scholar
  37. 37.
    Zimmermann S, Steding G, Emmen JM, Brinkmann AO, Nayernia K, Holstein AF, Engel W, Adham IM. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol. 1999;13:681–691.CrossRefPubMedGoogle Scholar
  38. 38.
    Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, Boettger-Tong HL, Bishop CE, Agoulnik AI. A transgenic insertion causing cryptorchidism in mice. Genesis. 2001;30:26–35.CrossRefPubMedGoogle Scholar
  39. 39.
    Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, Bathgate RA, Hsueh AJ. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem. 2002;277:31283–31286.CrossRefPubMedGoogle Scholar
  40. 40.
    Feng S, Bogatcheva NV, Kamat AA, Agoulnik AI. Genetic targeting of relaxin and insl3 signaling in mice. Ann N Y Acad Sci. 2005;1041:82–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Kamat AA, Feng S, Bogatcheva NV, Truong A, Bishop CE, Agoulnik AI. Genetic targeting of relaxin and insulin-like factor 3 receptors in mice. Endocrinology. 2004;145:4712–4720.CrossRefPubMedGoogle Scholar
  42. 42.
    Liu C, Eriste E, Sutton S, Chen J, Roland B, Kuei C, Farmer N, Jornvall H, Sillard R, Lovenberg TW. Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem. 2003;278:50754–50764.PubMedCrossRefGoogle Scholar
  43. 43.
    Liu C, Chen J, Sutton S, Roland B, Kuei C, Farmer N, Sillard R, Lovenberg TW. Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem. 2003;278:50765–50770.PubMedCrossRefGoogle Scholar
  44. 44.
    Hurley WL, Doane RM, O'Day-Bowman MB, Winn RJ, Mojonnier LE, Sherwood OD. Effect of relaxin on mammary development in ovariectomized pregnant gilts. Endocrinology. 1991;128:1285–1290.PubMedCrossRefGoogle Scholar
  45. 45.
    Bagnell CA, Frando LB, Downey BR, Tsang BK, Ainsworth L. Localization of relaxin in the pig follicle during preovulatory development. Biol Reprod. 1987;37:235–240.PubMedCrossRefGoogle Scholar
  46. 46.
    Einspanier A, Zarreh-Hoshyari-Khah MR, Balvers M, Kerr L, Fuhrmann K, Ivell R. Local relaxin biosynthesis in the ovary and uterus through the oestrous cycle and early pregnancy in the female marmoset monkey (Callithrix jacchus). Hum Reprod. 1997;12:1325–1337.CrossRefPubMedGoogle Scholar
  47. 47.
    Blankenship T, Stewart DR, Benirschke K, King B, Lasley BL. Immunocytochemical localization of nonluteal ovarian relaxin. J Reprod Med. 1994;39:235–240.PubMedGoogle Scholar
  48. 48.
    Zhang Q, Bagnell CA. Relaxin stimulation of porcine granulosa cell deoxyribonucleic acid synthesis in vitro: interactions with insulin and insulin-like growth factor I. Endocrinology. 1993;132:1643–1650.PubMedCrossRefGoogle Scholar
  49. 49.
    Shirota K, Tateishi K, Koji T, Hishikawa Y, Hachisuga T, Kuroki M, Kawarabayashi T. Early human preantral follicles have relaxin and relaxin receptor (LGR7), and relaxin promotes their development. J Clin Endocrinol Metab. 2005;90:516–521.PubMedCrossRefGoogle Scholar
  50. 50.
    Kawamura K, Kumagai J, Sudo S, Chun SY, Pisarska M, Morita H, Toppari J, Fu P, Wade JD, Bathgate RA, Hsueh AJ. Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci U S A. 2004;101:7323–7328.CrossRefPubMedGoogle Scholar
  51. 51.
    Stewart DR, Celniker AC, Taylor CA, Jr., Cragun JR, Overstreet JW, Lasley BL. Relaxin in the peri-implantation period. J Clin Endocrinol Metab. 1990;70:1771–1773.PubMedCrossRefGoogle Scholar
  52. 52.
    Dimitriadis E, Stoikos C, Baca M, Fairlie WD, McCoubrie JE, Salamonsen LA. Relaxin and prostaglandin E(2) regulate interleukin 11 during human endometrial stromal cell decidualization. J Clin Endocrinol Metab. 2005;90:3458–3465.CrossRefPubMedGoogle Scholar
  53. 53.
    Taylor MJ, Clark CL. Evidence for a novel source of relaxin: atrial cardiocytes. J Endocrinol. 1994;143:R5–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Du XJ, Samuel CS, Gao XM, Zhao L, Parry LJ, Tregear GW. Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res. 2003;57:395–404.CrossRefPubMedGoogle Scholar
  55. 55.
    Lekgabe ED, Kiriazis H, Zhao C, Xu Q, Moore XL, Su Y, Bathgate RAD, Du X-J, Samuel CS. Relaxin Reverses Cardiac and Renal Fibrosis in Spontaneously Hypertensive Rats. Hypertension. 2005;46:412–418.CrossRefPubMedGoogle Scholar
  56. 56.
    Samuel CS, Zhao C, Bond CP, Hewitson TD, Amento EP, Summers RJ. Relaxin-1-deficient mice develop an age-related progression of renal fibrosis. Kidney Int. 2004;65:2054–2064.CrossRefPubMedGoogle Scholar
  57. 57.
    Unemori EN, Pickford LB, Salles AL, Piercy CE, Grove BH, Erikson ME, Amento EP. Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest. 1996;98:2739–2745.PubMedCrossRefGoogle Scholar
  58. 58.
    Samuel CS, Unemori EN, Mookerjee I, Bathgate RAD, Layfield SL, Mak J, Tregear GW, Du X-J. Relaxin Modulates Cardiac Fibroblast Proliferation, Differentiation, and Collagen Production and Reverses Cardiac Fibrosis in Vivo. Endocrinology. 2004;145:4125–4133.CrossRefPubMedGoogle Scholar
  59. 59.
    Bani D, Baronti R, Vannacci A, Bigazzi M, Sacchi TB, Mannaioni PF, Masini E. Inhibitory effects of relaxin on human basophils activated by stimulation of the Fc epsilon receptor. The role of nitric oxide. Int Immunopharmacol. 2002;2:1195–1204.CrossRefPubMedGoogle Scholar
  60. 60.
    Masini E, Bani D, Bigazzi M, Mannaioni PF, Bani-Sacchi T. Effects of relaxin on mast cells. In vitro and in vivo studies in rats and guinea pigs. J Clin Invest. 1994;94:1974–1980.PubMedCrossRefGoogle Scholar
  61. 61.
    Bani-Sacchi T, Bigazzi M, Bani D, Mannaioni PF, Masini E. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol. 1995;116:1589–1594.PubMedGoogle Scholar
  62. 62.
    Bani D, Ballati L, Masini E, Bigazzi M, Sacchi TB. Relaxin counteracts asthma-like reaction induced by inhaled antigen in sensitized guinea pigs. Endocrinology. 1997;138:1909-1915.Google Scholar
  63. 63.
    Masini E, Bani D, Bello MG, Bigazzi M, Mannaioni PF, Sacchi TB. Relaxin counteracts myocardial damage induced by ischemia-reperfusion in isolated guinea pig hearts: evidence for an involvement of nitric oxide. Endocrinology. 1997;138:4713–4720.CrossRefPubMedGoogle Scholar
  64. 64.
    Garber SL, Mirochnik Y, Brecklin C, Slobodskoy L, Arruda JA, Dunea G. Effect of relaxin in two models of renal mass reduction. Am J Nephrol. 2003;23:8–12.CrossRefPubMedGoogle Scholar
  65. 65.
    Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJ, Unemori EN, Iredale JP. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut. 2001;49:577–583.Google Scholar
  66. 66.
    Samuel CS, Zhao C, Bathgate RA, Bond CP, Burton MD, Parry LJ, Summers RJ, Tang ML, Amento EP, Tregear GW. Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. Faseb J. 2003;17:121–123.PubMedGoogle Scholar
  67. 67.
    Palejwala S, Tseng L, Wojtczuk A, Weiss G, Goldsmith LT. Relaxin Gene and Protein Expression and Its Regulation of Procollagenase and Vascular Endothelial Growth Factor in Human Endometrial Cells. Biol Reprod. 2002;66:1743–1748.CrossRefPubMedGoogle Scholar
  68. 68.
    KOOS RD, KAZI AA, ROBERSON MS, JONES JM. New Insight into the Transcriptional Regulation of Vascular Endothelial Growth Factor Expression in the Endometrium by Estrogen and Relaxin. Ann NY Acad Sci. 2005;1041:233–247.CrossRefGoogle Scholar
  69. 69.
    Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, Chisholm V, Hillan KJ, Schwall RH. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med. 1998;4:336–340.CrossRefPubMedGoogle Scholar
  70. 70.
    Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.CrossRefPubMedGoogle Scholar
  71. 71.
    Li Y, Negishi S, Sakamoto M, Usas A, Huard J. The use of relaxin improves healing in injured muscle. Ann N Y Acad Sci. 2005;1041:395–397.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Jae-Il Park
    • 1
  • Chia Lin Chang
    • 1
  • Sheau Yu Teddy Hsu
    • 1
    • 2
    Email author
  1. 1.Division of Reproductive Biology, Department of Obstetrics and Gynecology, School of MedicineStanford UniversityStanfordUSA
  2. 2.Department of Obstetrics and Gynecology, School of MedicineStanford UniversityStanfordUSA

Personalised recommendations