Female Reproductive Tract

Matrix Metalloproteinases and Their Tissue Inhibitors in the Developing Neonatal Mouse Uterus

Abstract
Postnatal development of the mouse uterus involves differentiation and development of the endometrial glands as well as the myometrium. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix breakdown and morphogenesis of many epitheliomesenchymal organs. As a first step to understand their roles in postnatal mouse uterine development, MMPs and TIMPs, found to be expressed in the neonatal mouse uterus by microarray analysis, were localized by in situ hybridization. MMP-2 mRNA was detected only in the uterine stroma, whereas MMP-10 mRNA was present only in the uterine epithelium from postnatal day (PND) 3 to PND 9. All other MMPs (MMP-11, MMP-14, MMP-23) and TIMPs 1-3 were detected in both epithelial and stromal cells of the endometrium, but not in the myometrium. Uterine extracts were then analyzed by gelatin and casein gel zymography to detect active gelatinases and stromelysins, respectively. Five major gelatinase bands of activity were detected and inhibited by the MMP inhibitors, EDTA or 1,10-phenanthroline, but not by PMSF, a serine protease inhibitor. Western blot analysis confirmed the presence of MMP-2 and MMP-9 protein in the uterus. Immunoreactive MMP-9 protein was detected only in the endometrial stroma, whereas immunoreactive MMP-2 was detected in both stroma and epithelium of the uterus. Casein zymography detected three major bands of activity (approximately 54, 63 and 80 kDa) that were inhibited by the serine protease inhibitor PMSF, not by the MMP inhibitors EDTA or 1,10-phenanthroline, suggesting they were serine proteases. These results support the hypothesis that MMPs and TIMPs regulate postnatal development of the mouse uterus.

Key words: Female Reproductive Tract • Developmental biology • Uterus

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