Relaxin: Antifibrotic Properties and Effects in Models of Disease

Abstract

Fibrosis (progressive scarring) is a leading cause of organ failure worldwide and causes loss of organ function when normal tissue is replaced with excess connective tissue. Several organs are prone to this process regardless of etiology. The pleiotropic hormone, relaxin, is emerging as a novel antifibrotic therapy. Relaxin has been shown to limit collagen production and reorganization, while stimulating increased collagen degradation. It not only prevents fibrogenesis, but also reduces established scarring.This review summarizes (1) the levels at which relaxin inhibits collagen production and existing collagen overexpression in induced models of fibrosis, and (2) the collagen-related phenotypes of relaxin-and LGR7-deficient mice. Recent studies on relaxin-deficient mice have established relaxin as an important, naturally occurring regulator of collagen turnover and provide new insights into the therapeutic potential of relaxin. Keywords: Collagen, Gene-knockout mice, Fibrosis, RelaxinOne of the most consistent biological effects of relaxin is its ability to stimulate the breakdown of collagen, a major component of all organs within the body. Relaxin not only stimulates collagen remodeling within the birth canal in preparation for parturition, 1 but acts on cells and tissues to inhibit fibrosis, the process of tissue scarring which is primarily the result of excessive collagen deposition.Fibrosis is a universal response to chronic injury and inflammation of several organs and manifests itself as excess accumulation of connective tissue resulting in an irreversible loss of tissue function when normal tissue is replaced by scar tissue. 12,13 Fibrosis exists in numerous forms, including vascular sclerosis, hepatic cirrhosis, pulmonary fibrosis and renal fibrosis. These forms of deep organ fibrosis are particularly serious because the progressive loss of organ function is a leading cause of mortality estimated to account for 45% of deaths in the United States between 1984 and 1989. 12 It is also noteworthy that the underlying pathology of fibrosis remains similar in all cases suggesting that insights into the pathogenesis of scarring in any one of these organs has important implications for our understanding of fibrosis in general.Rel axin is a dimeric peptide hormone that is structurally related to the insulin family of peptides and has a diverse range of biological actions in several species. 1-9 Discovered almost 80 years ago, relaxin was found to be primarily produced in the ovary and/or placenta during pregnancy and was initially regarded as a hormone of pregnancy. 1 Humans and higher primates have three relaxin genes, designated as H1, H2 and H3 relaxin, 10 while two relaxin genes, relaxin-1 and relaxin-3, exist in rodents and are equivalent to H2 and H3 relaxin, respectively. The H2 relaxin protein (or relaxin-1 in rodents) is the major circulating and stored form of relaxin in each respective species and, therefore, will be the forms of relaxin referred to in this review. The H3 relaxin gene (or relaxin-3 ...

Relaxin Regulates MMP Expression and Promotes Satellite Cell Mobilization During Muscle Healing in Both Young and Aged Mice

“…The accelerated angiogenesis and controlled inflammation observed in our relaxintreated samples should have contributed to this modified microenvironment; a similar mechanism may also exist in the younger muscle. We suggest that this relaxin-modified microenvironment in the skeletal muscle can be related with the neutralizing effect of relaxin to TGF-␤1 activity and production, 38,70 because TGF-␤1 has been identified as a determining factor in creating the hostile microenvironment in the aged muscle.…”

“…27,[33][34][35][36][37] The mechanism behind the antifibrotic effect of relaxin is still unclear, but it has been discovered to prevent the influence of some profibrotic factors (ie, TGF-␤1, angiotensin II/Ang II, and interleukin-1␤) 35,38 -40 and stimulate the activation of MMPs in some tissues. 38 Recent in vitro studies suggested that relaxin administration improves myogenic differentiation of primary murine cardiomyocyte cell cultures. 41 Evidence from in vivo studies suggested that relaxin can favor cardiac muscle tissue remodeling and myocardial performance by inducing neoangiogenesis and ECM turnover in postinfarction heart repair.…”

Optimization of Radioimmunotherapy of Solid Tumors: Biological Impediments and Their Modulation

“…Relaxin, a peptide hormone primarily produced in the ovary and placenta during pregnancy, can alternatively be used to modulate collagen in tumor interstitium. Relaxin is a pleiotropic hormone that is involved in collagen remodeling by its action on fibroblasts, where it inhibits collagen synthesis and secretion and up-regulates matrix metalloproteinases (75). In fact, due to its antifibrotic properties, relaxin is used clinically in the treatment of scleroderma (76).…”

Preparation of canine relaxin by Fmoc-solid phase synthesis and regioselective disulfide bond formation within the A- and B-chains

“…More recently, our group and others have shown that locally produced relaxin has much wider actions, including roles in the cardiovascular [4,5] and central nervous systems [6,7] and an essential role in collagen turnover [8]. These actions of relaxin are mediated via a leucine-rich repeat-containing G-protein coupled receptor, known as LGR7 [9], which has more recently been re-named relaxin family peptide 1 (RXFP1) receptor [10].…”