Advertisement

The Effects of Relaxin on Extracellular Matrix Remodeling in Health and Fibrotic Disease

  • Chrishan S. Samuel
  • Edna D. Lekgabe
  • Ishanee Mookerjee
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 612)

Abstract

Since its discovery as a reproductive hormone 80 years ago, relaxin has been implicated in a number of pregnancy-related functions involving extracellular matrix (ECM) turnover and collagen degradation. It is now becoming evident that relaxin’s ability to reduce matrix synthesis and increase ECM degradation has important implications in several nonreproductive organs, including the heart, lung, kidney, liver and skin. The identification of relaxin and RXFP1 (Relaxin family peptide receptor-1) mRNA and/or binding sites in cells or vessels of these nonreproductive tissues, has confirmed them as targets for relaxin binding and activity. Recent studies on Rln1 and Rxfp1 gene-knockout mice have established relaxin as an important naturally occurring and protective moderator of collagen turnover, leading to improved organ structure and function. Furthermore, through its ability to regulate the ECM and in particular, collagen at multiple levels, relaxin has emerged as a potent anti-fibrotic therapy, with rapid-occurring efficacy. It not only prevents fibrogenesis, but also reduces established scarring (fibrosis), which is a leading cause of organ failure and affects several tissues regardless of etiology. This chapter will summarize these coherent findings as a means of highlighting the significance and therapeutic potential of relaxin.

Keywords

Collagen Accumulation Extracellular Matrix Remodel Collagen Turnover Allergic Airway Disease Antifibrotic Effect 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bathgate RAD, Hsueh AJ, Sherwood OD. Physiology and Molecular Biology of the Relaxin Peptide Family. In: Knobil E, Neill JD, eds. Physiology of Reproduction. 3rd ed. San Diego: Elsevier 2006:679–770.Google Scholar
  2. 2.
    Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev 2004;25(2):205–234.PubMedCrossRefGoogle Scholar
  3. 3.
    Hudson P, Haley J, John M et al. Structure of a genomic clone encoding biologically active human relaxin. Nature 1983;301(5901):628–631.PubMedCrossRefGoogle Scholar
  4. 4.
    Hudson P, John M, Crawford R et al. Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of cDNA clones. EMBO J 1984;3(10):2333–2339.PubMedGoogle Scholar
  5. 5.
    Bathgate RA, Samuel CS, Burazin TC et al. Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J Biol Chem 2002;277(2):1148–1157.PubMedCrossRefGoogle Scholar
  6. 6.
    Hsu SY, Nakabayashi K, Nishi S et al. Activation of orphan receptors by the hormone relaxin. Science 2002;295(5555):671–674.PubMedCrossRefGoogle Scholar
  7. 7.
    Liu C, Eriste E, Sutton S et al. Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem 2003;278(50):50754–50764.PubMedCrossRefGoogle Scholar
  8. 8.
    Liu C, Chen J, Sutton S et al. Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem 2003;278(50):50765–50770.PubMedCrossRefGoogle Scholar
  9. 9.
    Alberts B. Molecular biology of the cell. 3rd edition ed. New York: Garland Publishing; 1994.Google Scholar
  10. 10.
    Grodzinsky AJ, Frank EH, Kim Y-J et al. The role of specific macromolecules in cell-matrix interactions and in matrix function: physicochemical and mechanical mediators of chondrocyte biosymthesis. In: Comper WD, ed. Extracellular Matrix Vol. 2., Molecular Components and Interactions. Amsterdam, The Netherlands: Harwood Academic Publishers; 1996:310–334.Google Scholar
  11. 11.
    Lin CQ, Bissell MJ. Multi-faceted regulation of cell differentiation by extracellular matrix. FASEB J 1993;7(9):737–743.PubMedGoogle Scholar
  12. 12.
    Rubin K, Gullberg D, Tomasini-Johansson B et al. Molecular recognition of the extracellular matrix by cell surface receptors. In: Kompa WD, ed. Extracellular Matrix Vol. 2., Molecular Components and Interactions. Amsterdam, The Netherlands: Harwood Academic Publishers; 1996:262–309.Google Scholar
  13. 13.
    Venstrom KA, Reichardt LF. Extracellular matrix. 2: Role of extracellular matrix molecules and their receptors in the nervous system. FASEB J 1993;7(11):996–1003.PubMedGoogle Scholar
  14. 14.
    Bosman FT, Stamenkovic I. Functional structure and composition of the extracellular matrix. J Pathol 2003;200(4):423–428.PubMedCrossRefGoogle Scholar
  15. 15.
    Bateman JF, Lamande SR, Ramshaw JAM. Collagen Superfamily. In: Kompa WD, ed. Extracellular Matrix Vol. 2., Molecular Components and Interactions. Amsterdam, The Netherlands: Harwood Academic Publishers; 1996:22–67.Google Scholar
  16. 16.
    Kadler KE, Holmes DF, Trotter JA et al. Collagen fibril formation. Biochem J 1996;316(Pt 1):1–11.PubMedGoogle Scholar
  17. 17.
    Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol 2000;15(3–4):290–301.PubMedCrossRefGoogle Scholar
  18. 18.
    Phan SH. The myofibroblast in pulmonary fibrosis. Chest 2002;122(6 Suppl):286S–289S.PubMedCrossRefGoogle Scholar
  19. 19.
    Samuel CS. Relaxin: antifibrotic properties and effects in models of disease. Clin Med Res 2005;3(4):241–249.PubMedGoogle Scholar
  20. 20.
    Hisaw F. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 1926;23:661–663.Google Scholar
  21. 21.
    Weiss M, Nagelschmidt M, Struck H. Relaxin and collagen metabolism. Horm Metab Res 1979;11(6):408–410.PubMedGoogle Scholar
  22. 22.
    Samuel CS, Butkus A, Coghlan JP et al. The effect of relaxin on collagen metabolism in the nonpregnant rat pubic symphysis: the influence of estrogen and progesterone in regulating relaxin activity. Endocrinology 1996;137(9):3884–3890.PubMedCrossRefGoogle Scholar
  23. 23.
    Wahl LM, Blandau RJ, Page RC. Effect of hormones on collagen metabolism and collagenase activity in the pubic symphysis ligament of the guinea pig. Endocrinology 1977;100(2):571–579.PubMedGoogle Scholar
  24. 24.
    Downing SJ, Sherwood OD. The physiological role of relaxin in the pregnant rat. I. The influence of relaxin on parturition. Endocrinology 1985;116(3):1200–1205.PubMedCrossRefGoogle Scholar
  25. 25.
    Downing SJ, Sherwood OD. The physiological role of relaxin in the pregnant rat. II. The influence of relaxin on uterine contractile activity. Endocrinology 1985;116(3):1206–1214.PubMedGoogle Scholar
  26. 26.
    Downing SJ, Sherwood OD. The physiological role of relaxin in the pregnant rat. III. The influence of relaxin on cervical extensibility. Endocrinology 1985;116(3):1215–1220.PubMedGoogle Scholar
  27. 27.
    Downing SJ, Sherwood OD. The physiological role of relaxin in the pregnant rat. IV The influence of relaxin on cervical collagen and glycosaminoglycans. Endocrinology 1986;118(2):471–479.PubMedGoogle Scholar
  28. 28.
    Ferraiolo BL, Cronin M, Bakhit C et al. The pharmacokinetics and pharmacodynamics of a human relaxin in the mouse pubic symphysis bioassay. Endocrinology 1989;125(6):2922–2926.PubMedGoogle Scholar
  29. 29.
    Samuel CS, Mookerjee I, Lekgabe ED. Actions of relaxin on nonreproductive tissues. Current Medicinal Chemistry-Immunology, Endocrine and Metabolic Agents 2005;5(5):391–402.CrossRefGoogle Scholar
  30. 30.
    Unemori EN, Amento EP. Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 1990;265(18):10681–10685.PubMedGoogle Scholar
  31. 31.
    Unemori EN, Pickford LB, Salles AL et al. 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(12):2739–2745.PubMedCrossRefGoogle Scholar
  32. 32.
    Palejwala S, Stein DE, Weiss G et al. Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway. Endocrinology 2001;142(8):3405–3413.PubMedCrossRefGoogle Scholar
  33. 33.
    Heeg MH, Koziolek MJ, Vasko R et al. The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int 2005;68(1):96–109.PubMedCrossRefGoogle Scholar
  34. 34.
    Williams EJ, Benyon RC, Trim N et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 2001;49(4):577–583.PubMedCrossRefGoogle Scholar
  35. 35.
    Bennett RG, Kharbanda KK, Tuma DJ. Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. Biochem Pharmacol 2003;66(5):867–874.PubMedCrossRefGoogle Scholar
  36. 36.
    Masterson R, Hewitson TD, Kelynack K et al. Relaxin down-regulates renal fibroblast function and promotes matrix remodeling in vitro. Nephrol Dial Transplant 2004;19(3):544–552.PubMedCrossRefGoogle Scholar
  37. 37.
    Samuel CS, Unemori EN, Mookerjee I et al. Relaxin modulates cardiac fibroblast proliferation, differentiation and collagen production and reverses cardiac fibrosis in vivo. Endocrinology 2004;145:4125–4133.PubMedCrossRefGoogle Scholar
  38. 38.
    Unemori EN, Bauer EA, Amento EP. Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts. J Invest Dermatol 1992;99(3):337–342.PubMedCrossRefGoogle Scholar
  39. 39.
    Unemori EN, Beck LS, Lee WP et al. Human relaxin decreases collagen accumulation in vivo in two rodent models of fibrosis. J Invest Dermatol 1993;101(3):280–285.PubMedCrossRefGoogle Scholar
  40. 40.
    Garber SL, Mirochnik Y, Brecklin CS et al. Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int 2001;59(3):876–882.PubMedCrossRefGoogle Scholar
  41. 41.
    Garber SL, Mirochnik Y, Brecklin C et al. Effect of relaxin in two models of renal mass reduction. Am J Nephrol 2003;23(1):8–12.PubMedCrossRefGoogle Scholar
  42. 42.
    McDonald GA, Sarkar P, Rennke H et al. Relaxin increases ubiquitin-dependent degradation of fibronec-tin in vitro and ameliorates renal fibrosis in vivo. Am J Physiol Renal Physiol 2003;285(1):F59–67.PubMedGoogle Scholar
  43. 43.
    Lekgabe ED, Kiriazis H, Zhao C et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension 2005;46(2):412–418.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang J, Qi YF, Geng B et al. Effect of relaxin on myocardial ischemia injury induced by isoproterenol. Peptides 2005;26(9):1632–1639.PubMedCrossRefGoogle Scholar
  45. 45.
    Bathgate RAD, Lin F, Hanson NF et al. Relaxin-3: Improved synthesis strategy and demonstration of its high affinity interaction with the relaxin receptor LGR7 both in vitro and in vivo. Biochemistry 2006;45(3):1043–1053.PubMedCrossRefGoogle Scholar
  46. 46.
    Silvertown JD, Walia JS, Summerlee AJ et al. Functional expression of mouse relaxin and mouse relaxin-3 in the lung from an Ebola virus glycoprotein-pseudotyped lentivirus via tracheal delivery. Endocrinology 2006;147(8):3797–3808.PubMedCrossRefGoogle Scholar
  47. 47.
    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(1):260–266.PubMedGoogle Scholar
  48. 48.
    Hwang JJ, Lee AB, Fields PA et al. 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(6):3034–3042.PubMedGoogle Scholar
  49. 49.
    Lee AB, Hwang JJ, Haab LM et al. 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(4):2386–2391.PubMedCrossRefGoogle Scholar
  50. 50.
    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(2):425–430.PubMedCrossRefGoogle Scholar
  51. 51.
    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(11):4726–4734.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhao L, Roche PJ, Gunnersen JM et al. Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology 1999;140(1):445–453.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhao L, Samuel CS, Tregear GW et al. Collagen studies in late pregnant relaxin null mice. Biol Reprod 2000;63(3):697–703.PubMedCrossRefGoogle Scholar
  54. 54.
    Krajnc-Franken MA, van Disseldorp AJ, Koenders JE et al. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 2004;24(2):687–696.PubMedCrossRefGoogle Scholar
  55. 55.
    Kamat AA, Feng S, Bogatcheva NV et al. Genetic targeting of relaxin and Insl3 receptors in mice. Endocrinology 2004;145(10):4712–4720.PubMedCrossRefGoogle Scholar
  56. 56.
    Samuel CS, Tian H, Zhao L et al. Relaxin is a key mediator of prostate growth and male reproductive tract development. Lab Invest 2003;83(7):1055–1067.PubMedCrossRefGoogle Scholar
  57. 57.
    Du XJ, Samuel CS, Gao XM et al. Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res 2003;57(2):395–404.PubMedCrossRefGoogle Scholar
  58. 58.
    Samuel CS, Zhao C, Bathgate RA et al. Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. FASEB J 2003;17(1):121–123.PubMedGoogle Scholar
  59. 59.
    Samuel CS, Zhao C, Bond CP et al. Relaxin-1-deficient mice develop an age-related progression of renal fibrosis. Kidney Int 2004;65(6):2054–2064.PubMedCrossRefGoogle Scholar
  60. 60.
    Samuel CS, Zhao C, Yang Q et al. The relaxin gene knockout mouse: a model of progressive scleroderma. J Invest Dermatol 2005;125(4):692–699.PubMedCrossRefGoogle Scholar
  61. 61.
    Lekgabe ED, Royce SG, Hewitson TD et al. The effects of relaxin and estrogen deficiency on collagen deposition and hypertrophy of nonreproductive organs. Endocrinology 2006—in press.Google Scholar
  62. 62.
    Temelkovski J, Hogan SP, Shepherd DP et al. An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax 1998;53(10):849–856.PubMedCrossRefGoogle Scholar
  63. 63.
    Mookerjee I, Solly NR, Royce SG et al. Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease. Endocrinology 2006;147(2):754–761.PubMedCrossRefGoogle Scholar
  64. 64.
    Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol 2002;283(5):F861–875.PubMedGoogle Scholar
  65. 65.
    Cochrane AL, Kett MM, Samuel CS et al. Renal structural and functional repair in a mouse model of reversal of ureteral obstruction. J Am Soc Nephrol 2005;16(12):3623–3630.PubMedCrossRefGoogle Scholar
  66. 66.
    Hewitson TD, Mookerjee I, Masterson R et al. Endogenous relaxin is a naturally occurring modulator of experimental renal tuubulointerstitial fibrosis. Endocrinology—in press.Google Scholar
  67. 67.
    Schnaper HW, Hayashida T, Hubchak SC et al. TGF-beta signal transduction and mcsangial cell fibrogcncsis. Am J Physiol Renal Physiol 2003;284(2):F243–252.PubMedGoogle Scholar
  68. 68.
    Zhang Q, Liu SH, Erikson M et al. Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem 2002;85(3):536–544.PubMedCrossRefGoogle Scholar
  69. 69.
    Dschietzig T, Bartsch C, Richter C et al. Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 2003;92(1):32–40.PubMedCrossRefGoogle Scholar
  70. 70.
    Nguyen BT, Yang L, Sanborn BM et al. Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3′,5′-monophosphate by relaxin. Mol Endocrinol 2003;17(6):1075–1084.PubMedCrossRefGoogle Scholar
  71. 71.
    Nguyen BT, Dessauer CW. Relaxin stimulates protein kinase C zeta translocation: requirement for cyclic adenosine 3′, 5′-monophosphate production. Mol Endocrinol 2005;19(4):1012–1023.PubMedCrossRefGoogle Scholar
  72. 72.
    Palejwala S, Stein D, Wojtczuk A et al. Demonstration of a relaxin receptor and relaxin-stimu-lated tyrosine phosphorylation in human lower uterine segment fibroblasts. Endocrinology 1998;139(3):1208–1212.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Chrishan S. Samuel
    • 1
  • Edna D. Lekgabe
    • 2
  • Ishanee Mookerjee
    • 2
  1. 1.Howard Florey InstituteUniversity of MelbourneRarkvilieAustralia
  2. 2.Howard Florey Institute of Experimental Physiology Medicine and Department of Biochemistry and Molecular BiologyUniversity of MelbourneParkvilleAustralia

Personalised recommendations