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Inhibition of Matrix Metalloproteinases Prevents the Synthesis of Insulin-Like Growth Factor Binding Protein-1 during Decidualization in the Baboon

Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois 60212-7313

Address all correspondence and requests for reprints to: Zuzana Strakova, Ph.D., The University of Illinois at Chicago, Department of Obstetrics and Gynecology, 820 South Wood Street (M/C 808), Chicago, Illinois 60612-7313. E-mail: zstrakov{at}uic.edu.

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-1ß (10 ng/ml) with steroid hormones [36 nM estradiol-17ß, 1 µM medroxyprogesterone acetate (P), and 100 ng/ml relaxin] induces in vitro IGFBP-1 synthesis. This study demonstrates that IL-1ß 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-1ß-induced pro-MMP-3 protein. The ERK and p38 MAPK pathways induced by IL-1ß regulate pro-MMP-3 because inhibitors PD98059 (20 µM) and SB203580 (1 µM) prevent its synthesis. The nuclear factor-B inhibitory peptide, SN50 (50 µg/ml), or proteasome inhibitor, MG-132 (1 µM), 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. -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 -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-1ß-induced MMPs and particularly MMP-3 may up-regulate IGFBP-1 by disrupting the actin cytoskeleton as a result of ECM degradation.

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