title: Raloxifene upregulated mesangial cell MMP-2 activity via ER-β through transcriptional regulation.
abstract: Raloxifene, a second-generation selective estrogen receptor modulator, exerts estrogen-like effects in specific tissues. In this present study, we examined the effect of raloxifene on mesangial cell matrix metalloproteinase-2 (MMP-2) activity in streptozotocin-induced diabetic mice. Raloxifene increased the MMP-2 level in a dose-dependent and receptor-mediated manner. An antibody against estrogen receptor-β (ER-β) blocked the effect of raloxifene on MMP-2 expression, suggesting that the effect of raloxifene on MMP-2 activity was mediated by ER-β. In addition, the transcription factor AP-2, that plays an important role in MMP-2 gene transcription, was overexpressed under raloxifene simulation. The effect of MMP-2 was blocked by a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, PD98059. Our results suggested that raloxifene-induced MMP-2 activity increases function through ERK/MAPK signaling via AP-2. In addition, we also found that the effect of raloxifene on MMP-2 expression was mediated via its binding to ER-β. However, at this stage of our investigation, (i) we could only show that both the binding to ER-β and the activation of the ERK/MAPK pathway impacted MMP-2 expression and (ii) we were unable to establish a relationship between ER-β binding and ERK/MAPK pathway activation.
authors.affiliation: Department of Endocrinology, The Affiliated Jiangyin People's Hospital, School of Medicine, Southeast University, Jiangyin, 214400, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.forename: Xin-Chi
authors.initials: XC
authors.lastname: Wu
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism / Q000473:pathology; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D047629:Estrogen Receptor beta; D047428:Protein Kinase Inhibitors; D050656:Transcription Factor AP-2; D019716:Tissue Inhibitor of Metalloproteinase-2; D020849:Raloxifene Hydrochloride; D020778:Matrix Metalloproteinase 2