{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T05:08:25Z","timestamp":1761714505081,"version":"build-2065373602"},"reference-count":51,"publisher":"CSIRO Publishing","issue":"9","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":2631,"URL":"https:\/\/doi.org\/10.1071\/journalslicense"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,13]]},"abstract":"<jats:p>Relaxin regulates cervical extracellular matrix (ECM) remodelling during pregnancy by modifying collagen and other ECM molecules by unknown mechanisms. We hypothesised that abnormal collagen remodelling in the cervix of pregnant relaxin-deficient (Rln1-\/-) mice is due to excessive collagen (Col1a1 and Col3a1) and decreased matrix metalloproteinases (Mmp2, Mmp9, Mmp13 and Mmp7) and oestrogen receptors (Esr1 and Esr2). Quantitative polymerase chain reaction, gelatinase zymography, MMP activity assays and histological staining evaluated changes in ECM in pregnant wildtype (Rln1+\/+) and Rln1-\/- mice. Cervical Col1a1, Col3a1 and total collagen increased in Rln1-\/- mice and were higher at term compared with Rln1+\/+ mice. This was not correlated with a decrease in gelatinase (Mmp2, Mmp9) expression or activity, Mmp7 or Mmp13 expression, which were all significantly higher in Rln1-\/- mice. In late pregnancy, circulating MMP2 and MMP9 were unchanged. Esr1 expression was highest in Rln1+\/+ and Rln1-\/- mice in late pregnancy, coinciding with a decrease in Esr2 in Rln1+\/+ but not Rln1-\/- mice. The relaxin receptor (Rxfp1) decreased slightly in late-pregnant Rln1+\/+ mice, but was significantly higher in Rln1-\/- mice. In summary, relaxin deficiency results in increased cervical collagen in late pregnancy, which is not explained by a reduction in Mmp expression or activity or decreased Rxfp1. However, an imbalance between Esr1 and Esr2 may be involved.<\/jats:p>","DOI":"10.1071\/rd17544","type":"journal-article","created":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T18:52:38Z","timestamp":1520967158000},"page":"1214-1224","source":"Crossref","is-referenced-by-count":3,"title":["Abnormal extracellular matrix remodelling in the cervix of pregnant relaxin-deficient mice is not associated with reduced matrix metalloproteinase expression or activity"],"prefix":"10.1071","volume":"30","author":[{"given":"Sarah A.","family":"Marshall","sequence":"first","affiliation":[{"name":"ASchool of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan T.","family":"McGuane","sequence":"additional","affiliation":[{"name":"ASchool of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu May","family":"Soh","sequence":"additional","affiliation":[{"name":"ASchool of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen M.","family":"Gehring","sequence":"additional","affiliation":[{"name":"ASchool of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Simpson","sequence":"additional","affiliation":[{"name":"ASchool of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura J.","family":"Parry","sequence":"additional","affiliation":[{"name":"ASchool of BioSciences, The University of Melbourne, Parkville, Vic. 3010, Australia."},{"name":"BCorresponding author. Email: ljparry@unimelb.edu.au"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"67","published-online":{"date-parts":[[2018,3,14]]},"reference":[{"issue":"5","key":"2025102819483722900_R1","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1095\/BIOLREPROD.102.012534","article-title":"Changes in water content, collagen degradation, collagen content, and concentration in repeated biopsies of the cervix of pregnant cows.","volume":"69","author":"Breeveld-Dwarkasing","year":"2003","journal-title":"Biol. Reprod."},{"issue":"4","key":"2025102819483722900_R2","first-page":"601","article-title":"Over expression of aromatase protein is highly related to MMPs levels in human breast carcinomas.","volume":"24","author":"Di","year":"2005","journal-title":"J. Exp. Clin. Cancer Res."},{"issue":"2","key":"2025102819483722900_R3","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1210\/ENDO-118-2-471","article-title":"The physiological role of relaxin in the pregnant rat. IV. The influence of relaxin on cervical collagen and glycosaminoglycans.","volume":"118","author":"Downing","year":"1986","journal-title":"Endocrinology"},{"issue":"2","key":"2025102819483722900_R4","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S0008-6363(02)00663-6","article-title":"Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype.","volume":"57","author":"Du","year":"2003","journal-title":"Cardiovasc. Res."},{"issue":"1","key":"2025102819483722900_R5","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1210\/EN.2005-0626","article-title":"Endocrine effects of relaxin overexpression in mice.","volume":"147","author":"Feng","year":"2006","journal-title":"Endocrinology"},{"issue":"1","key":"2025102819483722900_R6","doi-asserted-by":"publisher","first-page":"39","DOI":"10.3181\/00379727-180-42140","article-title":"Stimulation of rat uterine collagen synthesis by relaxin.","volume":"180","author":"Frieden","year":"1985","journal-title":"Proc. Soc. Exp. Biol. Med."},{"issue":"13","key":"2025102819483722900_R7","doi-asserted-by":"publisher","first-page":"4685","DOI":"10.1073\/PNAS.0400776101","article-title":"Relaxin regulation of endometrial structure and function in the rhesus monkey.","volume":"101","author":"Goldsmith","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"12","key":"2025102819483722900_R8","doi-asserted-by":"publisher","first-page":"5566","DOI":"10.1210\/ENDO.140.12.7179","article-title":"The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens.","volume":"140","author":"Hall","year":"1999","journal-title":"Endocrinology"},{"issue":"2","key":"2025102819483722900_R9","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/J.ARCHORALBIO.2007.08.010","article-title":"Relaxin stimulates MMP-2 and alpha-smooth muscle actin expression by human periodontal ligament cells.","volume":"53","author":"Henneman","year":"2008","journal-title":"Arch. Oral Biol."},{"issue":"3","key":"2025102819483722900_R10","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1210\/EN.2010-1105","article-title":"The molecular mechanisms of cervical ripening differ between term and preterm birth.","volume":"152","author":"Holt","year":"2011","journal-title":"Endocrinology"},{"issue":"2","key":"2025102819483722900_R11","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/J.1582-4934.2006.TB00415.X","article-title":"MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors.","volume":"10","author":"Jinga","year":"2006","journal-title":"J. Cell. Mol. Med."},{"issue":"4","key":"2025102819483722900_R12","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1095\/BIOLREPROD.114.127209","article-title":"Conditional deletion of the relaxin receptor gene in cells of smooth muscle lineage affects lower reproductive tract in pregnant mice.","volume":"92","author":"Kaftanovskaya","year":"2015","journal-title":"Biol. Reprod."},{"issue":"10","key":"2025102819483722900_R13","doi-asserted-by":"publisher","first-page":"4712","DOI":"10.1210\/EN.2004-0515","article-title":"Genetic targeting of relaxin and insulin-like factor 3 receptors in mice.","volume":"145","author":"Kamat","year":"2004","journal-title":"Endocrinology"},{"issue":"2","key":"2025102819483722900_R14","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3349\/YMJ.2017.58.2.415","article-title":"Relaxin modulates the expression of MMPs and TIMPs in fibroblasts of patients with carpal tunnel syndrome.","volume":"58","author":"Kang","year":"2017","journal-title":"Yonsei Med. J."},{"key":"2025102819483722900_R15","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1111\/J.1749-6632.2009.03830.X","article-title":"Matrix metalloproteinase induction by relaxin causes cartilage matrix degradation in target synovial joints: receptor profiles correlate with matrix turnover.","volume":"1160","author":"Kapila","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"issue":"2","key":"2025102819483722900_R16","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1128\/MCB.24.2.687-696.2004","article-title":"Impaired nipple development and parturition in LGR7 knockout mice.","volume":"24","author":"Krajnc-Franken","year":"2004","journal-title":"Mol. Cell. Biol."},{"issue":"4","key":"2025102819483722900_R17","first-page":"2386","article-title":"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.","volume":"130","author":"Lee","year":"1992","journal-title":"Endocrinology"},{"issue":"9","key":"2025102819483722900_R18","doi-asserted-by":"publisher","first-page":"3941","DOI":"10.1210\/ENDO.142.9.8387","article-title":"Relaxin increases secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 during uterine and cervical growth and remodeling in the pig.","volume":"142","author":"Lenhart","year":"2001","journal-title":"Endocrinology"},{"issue":"1","key":"2025102819483722900_R19","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1210\/ENDO.143.1.8562","article-title":"Relaxin increases secretion of tissue inhibitor of matrix metalloproteinase-1 and -2 during uterine and cervical growth and remodeling in the pig.","volume":"143","author":"Lenhart","year":"2002","journal-title":"Endocrinology"},{"issue":"23","key":"2025102819483722900_R20","doi-asserted-by":"publisher","first-page":"8657","DOI":"10.1158\/0008-5472.CAN-04-3019","article-title":"Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets alpha1-antitrypsin serpin.","volume":"64","author":"Li","year":"2004","journal-title":"Cancer Res."},{"issue":"6","key":"2025102819483722900_R21","first-page":"981","article-title":"The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening.","volume":"13","author":"Mahendroo","year":"1999","journal-title":"Mol. Endocrinol."},{"issue":"9","key":"2025102819483722900_R22","doi-asserted-by":"publisher","first-page":"R847","DOI":"10.1152\/AJPREGU.00506.2015","article-title":"Relaxin deficiency attenuates pregnancy-induced adaptation of the mesenteric artery to angiotensin II in mice.","volume":"310","author":"Marshall","year":"2016","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol,"},{"issue":"1","key":"2025102819483722900_R23","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/S12958-016-0148-Y","article-title":"Relaxin deficiency results in increased expression of angiogenesis- and remodelling-related genes in the uterus of early pregnant mice but does not affect endometrial angiogenesis prior to implantation.","volume":"14","author":"Marshall","year":"2016","journal-title":"Reprod. Biol. Endocrinol."},{"key":"2025102819483722900_R24","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1111\/J.1749-6632.2009.04048.X","article-title":"Relaxin receptor LGR7 (RXFP1) is regulated by estrogen.","volume":"1160","author":"Maseelall","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"issue":"3","key":"2025102819483722900_R25","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1093\/NDT\/GFG598","article-title":"Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro.","volume":"19","author":"Masterson","year":"2004","journal-title":"Nephrol. Dial. Transplant."},{"issue":"5","key":"2025102819483722900_R26","doi-asserted-by":"publisher","first-page":"2399","DOI":"10.2353\/AJPATH.2010.091121","article-title":"Relaxin regulates MMP expression and promotes satellite cell mobilization during muscle healing in both young and aged mice.","volume":"177","author":"Mu","year":"2010","journal-title":"Am. J. Pathol."},{"issue":"5","key":"2025102819483722900_R27","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1095\/BIOLREPROD53.5.1030","article-title":"Relaxin stimulates interstitial collagenase activity in cultured uterine cervical cells from nonpregnant and pregnant but not immature guinea pigs; estradiol-17 beta restores relaxin\u2019s effect in immature cervical cells.","volume":"53","author":"Mushayandebvu","year":"1995","journal-title":"Biol. Reprod."},{"issue":"13","key":"2025102819483722900_R28","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1096\/FJ.06-6263COM","article-title":"Evidence for local relaxin ligand\u2013receptor expression and function in arteries.","volume":"20","author":"Novak","year":"2006","journal-title":"FASEB J."},{"issue":"2","key":"2025102819483722900_R29","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3181\/00379727-152-39377","article-title":"Radioimmunoassay (RIA) of relaxin in sera of various species using an antiserum to porcine relaxin.","volume":"152","author":"O\u2019Byrne","year":"1976","journal-title":"Proc. Soc. Exp. Biol. Med."},{"issue":"4","key":"2025102819483722900_R30","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1210\/ENDO-129-4-1967","article-title":"Hormonal control of the cervix in pregnant gilts. III. Relaxin\u2019s influence on cervical biochemical properties in ovariectomized hormone-treated pregnant gilts.","volume":"129","author":"O\u2019Day-Bowman","year":"1991","journal-title":"Endocrinology"},{"issue":"8","key":"2025102819483722900_R31","doi-asserted-by":"publisher","first-page":"3405","DOI":"10.1210\/ENDO.142.8.8295","article-title":"Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway.","volume":"142","author":"Palejwala","year":"2001","journal-title":"Endocrinology"},{"issue":"6","key":"2025102819483722900_R32","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1095\/BIOLREPROD66.6.1743","article-title":"Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells.","volume":"66","author":"Palejwala","year":"2002","journal-title":"Biol. Reprod."},{"key":"2025102819483722900_R33","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1007\/978-0-387-74672-2_4","article-title":"Relaxin physiology in the female reproductive tract during pregnancy.","volume":"612","author":"Parry","year":"2007","journal-title":"Adv. Exp. Med. Biol."},{"issue":"1","key":"2025102819483722900_R34","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1196\/ANNALS.1282.013","article-title":"Mechanisms of relaxin action in the reproductive tract: studies in the relaxin-deficient (Rlx-\/-) mouse.","volume":"1041","author":"Parry","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"issue":"4","key":"2025102819483722900_R35","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1071\/RD08243","article-title":"Normal mammary gland growth and lactation capacity in pregnant relaxin-deficient mice.","volume":"21","author":"Parry","year":"2009","journal-title":"Reprod. Fertil. Dev."},{"issue":"6","key":"2025102819483722900_R36","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1095\/BIOLREPROD.102.003392","article-title":"Treatment of rats with 17beta-estradiol or relaxin rapidly inhibits uterine estrogen receptor beta1 and beta2 messenger ribonucleic acid levels.","volume":"67","author":"Pillai","year":"2002","journal-title":"Biol. Reprod."},{"issue":"3","key":"2025102819483722900_R37","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1677\/JOE.0.0570413","article-title":"The effect of pregnancy on the collagen of the uterine cervix of the mouse.","volume":"57","author":"Rimmer","year":"1973","journal-title":"J. Endocrinol."},{"issue":"9","key":"2025102819483722900_R38","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.1210\/EN.2004-0209","article-title":"Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo.","volume":"145","author":"Samuel","year":"2004","journal-title":"Endocrinology"},{"key":"2025102819483722900_R39"},{"issue":"10","key":"2025102819483722900_R40","doi-asserted-by":"publisher","first-page":"4272","DOI":"10.1210\/EN.2003-0548","article-title":"Inhibition of oxytocin receptor and estrogen receptor-a expression, but not relaxin receptors (LGR7), in the myometrium of late pregnant relaxin gene knockout mice.","volume":"144","author":"Siebel","year":"2003","journal-title":"Endocrinology"},{"issue":"12","key":"2025102819483722900_R41","doi-asserted-by":"publisher","first-page":"6054","DOI":"10.1210\/EN.2012-1577","article-title":"Relaxin regulates hyaluronan synthesis and aquaporins in the cervix of late pregnant mice.","volume":"153","author":"Soh","year":"2012","journal-title":"Endocrinology"},{"key":"2025102819483722900_R42","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1146\/ANNUREV.CELLBIO.17.1.463","article-title":"How matrix metalloproteinases regulate cell behavior.","volume":"17","author":"Sternlicht","year":"2001","journal-title":"Annu. Rev. Cell Dev. Biol."},{"issue":"3","key":"2025102819483722900_R43","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1095\/BIOLREPROD.102.005116","article-title":"Increased level of matrix metalloproteinases 2 and 9 in the ripening process of the human cervix.","volume":"67","author":"Stygar","year":"2002","journal-title":"Biol. Reprod."},{"issue":"18","key":"2025102819483722900_R44","doi-asserted-by":"crossref","first-page":"10681","DOI":"10.1016\/S0021-9258(18)87000-4","article-title":"Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts.","volume":"265","author":"Unemori","year":"1990","journal-title":"J. Biol. Chem."},{"issue":"3","key":"2025102819483722900_R45","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1111\/1523-1747.EP12616665","article-title":"Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts.","volume":"99","author":"Unemori","year":"1992","journal-title":"J. Invest. Dermatol."},{"issue":"12","key":"2025102819483722900_R46","doi-asserted-by":"publisher","first-page":"2739","DOI":"10.1172\/JCI119099","article-title":"Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo.","volume":"98","author":"Unemori","year":"1996","journal-title":"J. Clin. Invest."},{"issue":"11","key":"2025102819483722900_R47","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1002\/MRD.20908","article-title":"MMP-2 expression precedes the final ripening process of the bovine cervix.","volume":"75","author":"van Engelen","year":"2008","journal-title":"Mol. Reprod. Dev."},{"issue":"5","key":"2025102819483722900_R48","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1210\/EN.2007-1176","article-title":"Relaxin acts on stromal cells to promote epithelial and stromal proliferation and inhibit apoptosis in the mouse cervix and vagina.","volume":"149","author":"Yao","year":"2008","journal-title":"Endocrinology"},{"issue":"6","key":"2025102819483722900_R49","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1210\/EN.2009-1327","article-title":"The effect of relaxin on cell proliferation in mouse cervix requires estrogen receptor {alpha} binding to estrogen response elements in stromal cells.","volume":"151","author":"Yao","year":"2010","journal-title":"Endocrinology"},{"issue":"1","key":"2025102819483722900_R50","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1210\/ENDO.140.1.6404","article-title":"Mice without a functional relaxin gene are unable to deliver milk to their pups.","volume":"140","author":"Zhao","year":"1999","journal-title":"Endocrinology"},{"issue":"3","key":"2025102819483722900_R51","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1095\/BIOLREPROD63.3.697","article-title":"Collagen studies in late pregnant relaxin null mice.","volume":"63","author":"Zhao","year":"2000","journal-title":"Biol. Reprod."}],"container-title":["Reproduction, Fertility and Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/connectsci.au\/rd\/article-pdf\/30\/9\/1214\/312163\/rd17544.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/connectsci.au\/rd\/article-pdf\/30\/9\/1214\/312163\/rd17544.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:48:44Z","timestamp":1761695324000},"score":1,"resource":{"primary":{"URL":"https:\/\/connectsci.au\/rd\/article\/30\/9\/1214\/50155\/Abnormal-extracellular-matrix-remodelling-in-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,14]]},"references-count":51,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2018,8,13]]}},"URL":"https:\/\/doi.org\/10.1071\/rd17544","relation":{},"ISSN":["1031-3613","1448-5990"],"issn-type":[{"type":"print","value":"1031-3613"},{"type":"electronic","value":"1448-5990"}],"subject":[],"published":{"date-parts":[[2018,3,14]]}}}