title: Inhibition of matrix metalloproteinases prevents the synthesis of insulin-like growth factor binding protein-1 during decidualization in the baboon.
abstract: During pregnancy in the primate, uterine stromal fibroblasts are transformed into decidual cells. Decidualization is associated with extensive remodeling of the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) play a pivotal role in ECM degradation. We hypothesized that MMPs also contribute to regulation of IGF binding protein-1 (IGFBP-1), a biochemical marker of primate decidual cells. We reported that IL-1beta (10 ng/ml) with steroid hormones [36 nm estradiol-17beta, 1 microm medroxyprogesterone acetate (P), and 100 ng/ml relaxin] induces in vitro IGFBP-1 synthesis. This study demonstrates that IL-1beta also induces stromelysin-1 (MMP-3) mRNA and synthesis of the latent form of MMP-3 (pro-MMP-3) protein in baboon stromal fibroblasts. In contrast, hormones (particularly P) negatively regulate MMP-3 because their addition decreases IL-1beta-induced pro-MMP-3 protein. The ERK and p38 MAPK pathways induced by IL-1beta regulate pro-MMP-3 because inhibitors PD98059 (20 microm) and SB203580 (1 microm) prevent its synthesis. The nuclear factor-kappaB inhibitory peptide, SN50 (50 microg/ml), or proteasome inhibitor, MG-132 (1 microm), did not inhibit pro-MMP-3 synthesis but appeared to enhance it. The role of MMPs in IGFBP-1 induction was investigated using a broad-spectrum MMP inhibitor, doxycycline, and specific MMP-3 inhibitor, N-Isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid (NNGH). Both inhibitors caused the dose-dependent decrease of IGFBP-1. alpha-Smooth muscle actin, which is down-regulated during decidualization, was partially up-regulated by doxycycline or N-Isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid. This suggests that alpha-smooth muscle actin is modulated by changes in ECM caused by the action of MMPs/MMP-3. Disruption of actin filaments enhances IGFBP-1 induction. Thus, our data imply that IL-1beta-induced MMPs and particularly MMP-3 may up-regulate IGFBP-1 by disrupting the actin cytoskeleton as a result of ECM degradation.
authors.affiliation: Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois 60612-7313, USA. zstrakov@uic.edu.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Strakova
authors.forename: Maciej
authors.initials: M
authors.lastname: Szmidt
authors.forename: Santha
authors.initials: S
authors.lastname: Srisuparp
authors.forename: Asgerally T
authors.initials: AT
authors.lastname: Fazleabas
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000096:biosynthesis* / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D010215:Papio; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology
chemical_list: D000199:Actins; D004792:Enzyme Precursors; D018970:Insulin-Like Growth Factor Binding Protein 1; D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D011374:Progesterone; D008666:Metalloendopeptidases; C048047:prostromelysin; D019278:Matrix Metalloproteinase 3