The Antifibrotic Role of Relaxin
Abstract
Relaxin, a polypeptide hormone of the insulin superfamily, is involved in the promotion of extracellular matrix remodeling. Emerging evidence supports a potential therapeutic role of relaxin in fibrotic diseases including liver. Relaxin has been shown to limit collagen production and promote collagen degradation. It not only prevents fibrogenesis, but also reduces established scarring. Together, these findings suggest that the liver is a target organ of relaxin. Therefore, the purpose of this review is to provide an overview of relaxin, its receptor, and their signaling with a focus on areas of potential translational research on fibrosis with emphasis on liver.References
1. Sherwood, O.D., Relaxin's physiological roles and other diverse actions. Endocr Rev, 2004. 25(2): p. 205-34.
2. Samuel, C.S., et al., Relaxin-1-deficient mice develop an age-related progression of renal fibrosis. Kidney Int, 2004. 65(6): p. 2054-64.
3. Mookerjee, I., et al., Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease. Endocrinology, 2006. 147(2): p. 754-61.
4. Bennett, R.G., et al., Relaxin decreases the severity of established hepatic fibrosis in mice. Liver International, 2014. 34(3): p. 416-426.
5. Sherwood, O.D., Relaxin's Physiological Roles and Other Diverse Actions. Endocr Rev, 2004. 25(2): p. 205-234.
6. Dschietzig, T., et al., Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics. Pharmacol Ther, 2006. 112(1): p. 38-56.
7. Bathgate, R.A., et al., International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev, 2006. 58(1): p. 7-31.
8. Hsu, S.Y., et al., Activation of orphan receptors by the hormone relaxin. Science, 2002. 295(5555): p. 671-4.
9. Singh, S. and R.G. Bennett, Relaxin signaling activates peroxisome proliferator-activated receptor gamma. Mol Cell Endocrinol, 2010. 315(1-2): p. 239-45.
10. Kumagai, J., et al., INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem, 2002. 277(35): p. 31283-6.
11. Liu, C., 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): p. 50754-64.
12. Liu, C., et al., Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem, 2003. 278(50): p. 50765-70.
13. Kohsaka, T., et al., Identification of specific relaxin-binding cells in the human female. Biol Reprod, 1998. 59(4): p. 991-9.
14. Ivell, R., et al., Immunoexpression of the relaxin receptor LGR7 in breast and uterine tissues of humans and primates. Reprod Biol Endocrinol, 2003. 1: p. 114.
15. Hombach-Klonisch, S., et al., INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes. Int J Oncol, 2003. 22(5): p. 993-1001.
16. Mazella, J., M. Tang, and L. Tseng, Disparate effects of relaxin and TGFbeta1: relaxin increases, but TGFbeta1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells. Hum Reprod, 2004. 19(7): p. 1513-8.
17. Kong, R.C., et al., Membrane receptors: structure and function of the relaxin family peptide receptors. Mol Cell Endocrinol. 320(1-2): p. 1-15.
18. Halls, M.L., et al., Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol, 2007. 150(6): p. 677-91.
19. Bennett, R.G., et al., Relaxin receptors in hepatic stellate cells and cirrhotic liver. Biochem Pharmacol, 2007. 73(7): p. 1033-40.
20. Hsu, S.Y., et al., 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(8): p. 1257-71.
21. Kobe, B. and J. Deisenhofer, Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats. Nature, 1993. 366(6457): p. 751-6.
22. Kobe, B. and A.V. Kajava, The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol, 2001. 11(6): p. 725-32.
23. Braddon, S.A., Relaxin-dependent adenosine 6',5'-monophosphate concentration changes in the mouse pubic symphysis. Endocrinology, 1978. 102(4): p. 1292-9.
24. Hsu, C.J., S.M. McCormack, and B.M. Sanborn, The effect of relaxin on cyclic adenosine 3',5'-monophosphate concentrations in rat myometrial cells in culture. Endocrinology, 1985. 116(5): p. 2029-35.
25. Halls, M.L., R.A.D. Bathgate, and R.J. Summers, Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms. Mol Pharmacol, 2006. 70(1): p. 214-226.
26. Singh, S., R.L. Simpson, and R.G. Bennett, Relaxin activates peroxisome proliferator-activated receptor gamma (PPARgamma) through a pathway involving PPARgamma coactivator 1alpha (PGC1alpha). J Biol Chem, 2015. 290(2): p. 950-9.
27. Singh, S. and R.G. Bennett, Relaxin family peptide receptor 1 activation stimulates peroxisome proliferator-activated receptor gamma. Ann N Y Acad Sci, 2009. 1160: p. 112-6.
28. Nguyen, B.T., et al., Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3',5'-monophosphate by relaxin. Mol Endocrinol, 2003. 17(6): p. 1075-84.
29. Halls, M.L., R.A. Bathgate, and R.J. Summers, Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol, 2006. 70(1): p. 214-26.
30. Nguyen, B.T. and C.W. Dessauer, Relaxin stimulates protein kinase C zeta translocation: requirement for cyclic adenosine 3',5'-monophosphate production. Mol Endocrinol, 2005. 19(4): p. 1012-23.
31. Bani, D., et al., Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension, 1998. 31(6): p. 1240-7.
32. Failli, P., et al., Relaxin up-regulates inducible nitric oxide synthase expression and nitric oxide generation in rat coronary endothelial cells. Faseb J, 2002. 16(2): p. 252-4.
33. Bani, D., et al., Relaxin up-regulates the nitric oxide biosynthetic pathway in the mouse uterus: involvement in the inhibition of myometrial contractility. Endocrinology, 1999. 140(10): p. 4434-41.
34. Nistri, S. and D. Bani, Relaxin receptors and nitric oxide synthases: search for the missing link. Reprod Biol Endocrinol, 2003. 1: p. 5.
35. Bartsch, O., B. Bartlick, and R. Ivell, Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod, 2001. 7(9): p. 799-809.
36. Bathgate, R.A., et al., Receptors for Relaxin Family Peptides. Ann NY Acad Sci, 2005. 1041(1): p. 61-76.
37. Zhang, Q., et al., Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem, 2002. 85(3): p. 536-44.
38. Dschietzig, T., 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): p. 32-40.
39. Wallace, K., A.D. Burt, and M.C. Wright, Liver fibrosis. Biochem J, 2008. 411(1): p. 1-18.
40. Friedman, S.L., Liver fibrosis -- from bench to bedside. J Hepatol, 2003. 38 Suppl 1: p. S38-53.
41. Marra, F., Hepatic stellate cells and the regulation of liver inflammation. J Hepatol, 1999. 31(6): p. 1120-30.
42. Milani, S., et al., Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology, 1990. 98(1): p. 175-84.
43. Bataller, R. and D.A. Brenner, Liver fibrosis. J Clin Invest, 2005. 115(2): p. 209-18.
44. Arthur, M.J., Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol, 2000. 279(2): p. G245-9.
45. Wang, Z., et al., Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. Hepatobiliary Pancreat Dis Int. 10(1): p. 64-71.
46. Bennett, R.G., K.K. Kharbanda, and D.J. Tuma, Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. Biochem Pharmacol, 2003. 66(5): p. 867-74.
47. Samuel, C.S., E.D. Lekgabe, and I. Mookerjee, The effects of relaxin on extracellular matrix remodeling in health and fibrotic disease. Adv Exp Med Biol, 2007. 612: p. 88-103.
48. Zhao, L., et al., Collagen studies in late pregnant relaxin null mice. Biol Reprod, 2000. 63(3): p. 697-703.
49. Samuel, C.S., et al., The relaxin gene knockout mouse: a model of progressive scleroderma. J Invest Dermatol, 2005. 125(4): p. 692-9.
50. Unemori, E.N. and E.P. Amento, Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem, 1990. 265(18): p. 10681-5.
51. Unemori, E.N., E.A. Bauer, and E.P. Amento, Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts. J Invest Dermatol, 1992. 99(3): p. 337-42.
52. Samuel, C.S., et al., Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. Faseb J, 2003. 17(1): p. 121-3.
53. Samuel, C.S., et al., Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology, 2004. 145(9): p. 4125-33.
54. Williams, E.J., et al., Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut, 2001. 49(4): p. 577-83.
55. Singh, S. and R.G. Bennett, Relaxin activation of PPAR [gamma] is ligand independent. The FASEB Journal, 2009. 23(1 Supplement): p. 706.3-706.3.
56. Singh, S. and R.G. Bennett, Dominant-negative and knockdown approaches to studying PPAR activity. Methods Mol Biol, 2013. 952: p. 87-98.
2. Samuel, C.S., et al., Relaxin-1-deficient mice develop an age-related progression of renal fibrosis. Kidney Int, 2004. 65(6): p. 2054-64.
3. Mookerjee, I., et al., Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease. Endocrinology, 2006. 147(2): p. 754-61.
4. Bennett, R.G., et al., Relaxin decreases the severity of established hepatic fibrosis in mice. Liver International, 2014. 34(3): p. 416-426.
5. Sherwood, O.D., Relaxin's Physiological Roles and Other Diverse Actions. Endocr Rev, 2004. 25(2): p. 205-234.
6. Dschietzig, T., et al., Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics. Pharmacol Ther, 2006. 112(1): p. 38-56.
7. Bathgate, R.A., et al., International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev, 2006. 58(1): p. 7-31.
8. Hsu, S.Y., et al., Activation of orphan receptors by the hormone relaxin. Science, 2002. 295(5555): p. 671-4.
9. Singh, S. and R.G. Bennett, Relaxin signaling activates peroxisome proliferator-activated receptor gamma. Mol Cell Endocrinol, 2010. 315(1-2): p. 239-45.
10. Kumagai, J., et al., INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem, 2002. 277(35): p. 31283-6.
11. Liu, C., 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): p. 50754-64.
12. Liu, C., et al., Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem, 2003. 278(50): p. 50765-70.
13. Kohsaka, T., et al., Identification of specific relaxin-binding cells in the human female. Biol Reprod, 1998. 59(4): p. 991-9.
14. Ivell, R., et al., Immunoexpression of the relaxin receptor LGR7 in breast and uterine tissues of humans and primates. Reprod Biol Endocrinol, 2003. 1: p. 114.
15. Hombach-Klonisch, S., et al., INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes. Int J Oncol, 2003. 22(5): p. 993-1001.
16. Mazella, J., M. Tang, and L. Tseng, Disparate effects of relaxin and TGFbeta1: relaxin increases, but TGFbeta1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells. Hum Reprod, 2004. 19(7): p. 1513-8.
17. Kong, R.C., et al., Membrane receptors: structure and function of the relaxin family peptide receptors. Mol Cell Endocrinol. 320(1-2): p. 1-15.
18. Halls, M.L., et al., Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol, 2007. 150(6): p. 677-91.
19. Bennett, R.G., et al., Relaxin receptors in hepatic stellate cells and cirrhotic liver. Biochem Pharmacol, 2007. 73(7): p. 1033-40.
20. Hsu, S.Y., et al., 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(8): p. 1257-71.
21. Kobe, B. and J. Deisenhofer, Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats. Nature, 1993. 366(6457): p. 751-6.
22. Kobe, B. and A.V. Kajava, The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol, 2001. 11(6): p. 725-32.
23. Braddon, S.A., Relaxin-dependent adenosine 6',5'-monophosphate concentration changes in the mouse pubic symphysis. Endocrinology, 1978. 102(4): p. 1292-9.
24. Hsu, C.J., S.M. McCormack, and B.M. Sanborn, The effect of relaxin on cyclic adenosine 3',5'-monophosphate concentrations in rat myometrial cells in culture. Endocrinology, 1985. 116(5): p. 2029-35.
25. Halls, M.L., R.A.D. Bathgate, and R.J. Summers, Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms. Mol Pharmacol, 2006. 70(1): p. 214-226.
26. Singh, S., R.L. Simpson, and R.G. Bennett, Relaxin activates peroxisome proliferator-activated receptor gamma (PPARgamma) through a pathway involving PPARgamma coactivator 1alpha (PGC1alpha). J Biol Chem, 2015. 290(2): p. 950-9.
27. Singh, S. and R.G. Bennett, Relaxin family peptide receptor 1 activation stimulates peroxisome proliferator-activated receptor gamma. Ann N Y Acad Sci, 2009. 1160: p. 112-6.
28. Nguyen, B.T., et al., Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3',5'-monophosphate by relaxin. Mol Endocrinol, 2003. 17(6): p. 1075-84.
29. Halls, M.L., R.A. Bathgate, and R.J. Summers, Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol, 2006. 70(1): p. 214-26.
30. Nguyen, B.T. and C.W. Dessauer, Relaxin stimulates protein kinase C zeta translocation: requirement for cyclic adenosine 3',5'-monophosphate production. Mol Endocrinol, 2005. 19(4): p. 1012-23.
31. Bani, D., et al., Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension, 1998. 31(6): p. 1240-7.
32. Failli, P., et al., Relaxin up-regulates inducible nitric oxide synthase expression and nitric oxide generation in rat coronary endothelial cells. Faseb J, 2002. 16(2): p. 252-4.
33. Bani, D., et al., Relaxin up-regulates the nitric oxide biosynthetic pathway in the mouse uterus: involvement in the inhibition of myometrial contractility. Endocrinology, 1999. 140(10): p. 4434-41.
34. Nistri, S. and D. Bani, Relaxin receptors and nitric oxide synthases: search for the missing link. Reprod Biol Endocrinol, 2003. 1: p. 5.
35. Bartsch, O., B. Bartlick, and R. Ivell, Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod, 2001. 7(9): p. 799-809.
36. Bathgate, R.A., et al., Receptors for Relaxin Family Peptides. Ann NY Acad Sci, 2005. 1041(1): p. 61-76.
37. Zhang, Q., et al., Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem, 2002. 85(3): p. 536-44.
38. Dschietzig, T., 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): p. 32-40.
39. Wallace, K., A.D. Burt, and M.C. Wright, Liver fibrosis. Biochem J, 2008. 411(1): p. 1-18.
40. Friedman, S.L., Liver fibrosis -- from bench to bedside. J Hepatol, 2003. 38 Suppl 1: p. S38-53.
41. Marra, F., Hepatic stellate cells and the regulation of liver inflammation. J Hepatol, 1999. 31(6): p. 1120-30.
42. Milani, S., et al., Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology, 1990. 98(1): p. 175-84.
43. Bataller, R. and D.A. Brenner, Liver fibrosis. J Clin Invest, 2005. 115(2): p. 209-18.
44. Arthur, M.J., Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol, 2000. 279(2): p. G245-9.
45. Wang, Z., et al., Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. Hepatobiliary Pancreat Dis Int. 10(1): p. 64-71.
46. Bennett, R.G., K.K. Kharbanda, and D.J. Tuma, Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. Biochem Pharmacol, 2003. 66(5): p. 867-74.
47. Samuel, C.S., E.D. Lekgabe, and I. Mookerjee, The effects of relaxin on extracellular matrix remodeling in health and fibrotic disease. Adv Exp Med Biol, 2007. 612: p. 88-103.
48. Zhao, L., et al., Collagen studies in late pregnant relaxin null mice. Biol Reprod, 2000. 63(3): p. 697-703.
49. Samuel, C.S., et al., The relaxin gene knockout mouse: a model of progressive scleroderma. J Invest Dermatol, 2005. 125(4): p. 692-9.
50. Unemori, E.N. and E.P. Amento, Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem, 1990. 265(18): p. 10681-5.
51. Unemori, E.N., E.A. Bauer, and E.P. Amento, Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts. J Invest Dermatol, 1992. 99(3): p. 337-42.
52. Samuel, C.S., et al., Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. Faseb J, 2003. 17(1): p. 121-3.
53. Samuel, C.S., et al., Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology, 2004. 145(9): p. 4125-33.
54. Williams, E.J., et al., Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut, 2001. 49(4): p. 577-83.
55. Singh, S. and R.G. Bennett, Relaxin activation of PPAR [gamma] is ligand independent. The FASEB Journal, 2009. 23(1 Supplement): p. 706.3-706.3.
56. Singh, S. and R.G. Bennett, Dominant-negative and knockdown approaches to studying PPAR activity. Methods Mol Biol, 2013. 952: p. 87-98.
Published
2016-07-14
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