Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Unemori, Elaine; Pickford, Lesley B.; Salles, Adam; Piercy, Christopher E.; Grove, Beverly H.; Erikson, Mark; Amento, Edward P.

doi:10.1172/jci119099

Cited by 323 publications

(302 citation statements)

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“…Therefore, it is possible that cells within the PC3-Luc-H2/eGFP tumors were exposed to sufficient levels of H2 relaxin within the tumor microenvironment so that proMMP-9 activity was downregulated. This biphasic effect of H2 relaxin on MMPs 27 and in other physiological systems [42][43][44] has been reported in other studies. It is interesting to note that H-59 cells, a lung carcinoma cell line, when stimulated with increasing doses of IGF-1 (related molecule to relaxin in the IGF family) between analogous doses of (0-100 ng/mL) demonstrates a similar biphasic regulation of activity of MMP-2.…”

Section: Discussionsupporting

confidence: 80%

“…Other investigators have observed that the effect of relaxin on MMP regulation appears to be cell-type specific. For example, the upregulation, 10,28 downregulation 39,40 and biphasic regulation 27 of MMPs by relaxin have been reported before. In tumor biology, MMPs have been implicated in a variety of processes: a) the degradation of the ECM allowing for cell migration; 41 b) the alteration of the ECM microenvironment resulting in changes of cellular behaviour; 41 and c) the modulation of biologically active molecules by direct cleavage, release from bound stores or modulation of the activity of tissue inhibitors of MMPs (TIMPs).…”

Section: Discussionmentioning

confidence: 71%

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H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

Silvertown

Sato

et al. 2005

Intl Journal of Cancer

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Our study reports a preliminary investigation into the role of human H2 relaxin in prostate tumor growth. A luciferase-expressing human prostate cancer cell line, PC-3, was generated and termed PC3-Luc. PC3-Luc cells were transduced with lentiviral vectors engineering the expression of either enhanced green fluorescent protein (eGFP) or both H2 relaxin and eGFP in a bicistronic format. These transduced cells were termed PC3-Luc-eGFP and PC3-Luc-H2/eGFP, respectively. To gauge effects, PC3-Luc-H2/eGFP and PC3-Luc-eGFP cells were injected into NOD/SCID mice and monitored over 6 weeks. PC-3 tumor xenografts overexpressing H2 relaxin exhibited greater tumor volumes compared to control tumors. Circulating H2 relaxin levels in sera increased with the relative size of the tumor, with moderately elevated H2 relaxin levels in mice bearing PC3-Luc-H2/eGFP tumors compared to PC3-Luc-eGFP tumors. Zymographic analysis demonstrated that proMMP-9 enzyme activity was significantly downregulated in H2 relaxin-overexpressing tumors. An advanced angiogenic phenotype was observed in H2 relaxin-overexpressing tumors indicated by greater intratumoral vascularization by immunohistochemical staining of endothelial cells with anti-mouse CD31. Moreover, PC3-Luc-H2/eGFP tumors exhibited increased VEGF transcript by reverse-transcription PCR, compared to basal levels in control animals. Taken together, our study provides the first account of a potential role of H2 relaxin in prostate tumor development. ' 2005 Wiley-Liss, Inc.Key words: PC-3; lentivirus; luciferase; VEGF; MMP-9; H2; prorelaxin In recent years, there has been increasing evidence that suggests a role of relaxin in carcinogenesis. Peptide hormones of the relaxin family are reported to be upregulated in a number of neoplasias, including thyroid, 1 breast, 2 gastrointestinal 3 and the reproductive system. 4,5 Many of the molecules characterized as downstream effectors of relaxin's physiological roles in the cardiovascular system and as agents involved in remodeling of connective tissue have also been linked with tumor growth and sustainability. 6 These molecules, including VEGF and NOS, for example, are established angiogenic agents that promote neovascularization and enhanced blood flow carrying oxygen and cellular nutrients to tumors. 7 The regulation of matrix metalloproteinases (MMPs) is the mechanism considered for relaxin's role in connective tissue remodeling during mammary gland involution, softening of reproductive tissues and dilation of the birth canal. 8 However, the regulation of these enzymes by relaxin have also been suggested as a mechanism for its role in facilitating cancer cell migration and invasion. [9][10][11] Although the biological significance of relaxin in the male remains elusive, the prostate gland appears to be relaxin's main source. 8 In the human, there are 3 relaxin alleles encoding 3 hormones, named H1, H2 and H3. While H2 and H3 relaxins are expressed in a number of tissues, in males their predominant expression is found in the prostate and bra...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 71%

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

Silvertown

Sato

et al. 2005

Intl Journal of Cancer

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“…Relaxin early (Unemori et al, 1996) 17 9 AG1879 early (Vittal et al, 2005) (Xiao, Zhang, Chen, Feng, & Wang, 2005) 19 1 rHGF early (Yaekashiwa et al, 1997) 19 2 PC-SOD early (Yamazaki et al, 1997) 19 3…”

Section: Idmentioning

confidence: 99%

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Moeller

Ask

Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

841

724

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Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.

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“…First, relaxin, the endothelial ET B receptor, and NO have an essential role in pregnancy-mediated renal vasodilation. Second, relaxin serves to upregulate MMP expression at least in fibroblasts (33). Third, vascular MMP, such as MMP-2, are able to process big ET at the gly-leu bond to ET with subsequent activation of endothelin receptors (34).…”

Section: Newer Aspects On Relaxin In Pregnancy and Preeclampsiamentioning

confidence: 99%

New Aspects in the Pathophysiology of Preeclampsia

Davison¹,

Homuth²,

Jeyabalan³

et al. 2004

Journal of the American Society of Nephrology

171

109

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Abstract. Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.The term preeclampsia refers to the new onset of hypertension (Ͼ140/90 mmHg) and proteinuria after 20 wk of gestation in previously normotensive, nonproteinuric women (1). The condition is common and occurs in~5% of pregnancies in the United States and Europe. Eclampsia is a life-threatening complication and is characterized by grand mal seizures. The term comes from the Greek word for lightning. A severe variant of preeclampsia also features hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). This condition occurs iñ 1 per 1000 pregnancies. Predisposing factors are a positive family history, hypertension, diabetes, preexisting renal disease, multiple pregnancies, and a poor obstetric history. Nephrologists are often called on to see preeclamptic women because of the severe BP elevation and renal disease. Thus, new clinical or experimental information on this condition is important information for nephrologists. Preeclampsia and Subsequent Cardiovascular RiskThe relevance of preeclampsia to the offspring is well recognized. Children who are born to preeclamptic mothers commonly have low birth weight, and their subsequent cardiovascular risk has been a vast investigational field. The mother's outcome has attracted less interest. Chesley, the father of modern preeclampsia research, was of the opinion that once the condition was over, the mothers had no greater risk of adverse long-term outcomes than women without preeclampsia from the general population (2). This issue may prove to be the only matter in which Chesley's opinion was erroneous. Several recent studies suggest that the converse is the case. Smith et al. (3) studied the pregnancy complications and the maternal risk of ischemic cardiac death in 129,290 births. They found that delivering an infant with low birth weight for gestational age increased the hazard ratio for ischemic heart disease o...

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Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.

Cited by 323 publications

References 31 publications

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

New Aspects in the Pathophysiology of Preeclampsia

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