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Identification and Characterization of Extracellular Matrix Metalloproteinase Inducer in Human Endometrium during the Menstrual Cycle in Vivo and in Vitro

Department of Biochemistry and Molecular Biology (Y.N., T.S., M.H., A.I.), School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan; Bio-oriented Technology Research Advancement Institution (M.H.), Minato-ku, Tokyo 105-0001, Japan; and Department of Obstetrics and Gynecology (T.H., K.O.), Hiroshima University School of Medicine, Minami-ku, Hiroshima 734-8551, Japan

Address all correspondence and requests for reprints to: Takashi Sato, Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: satotak{at}ps.toyaku.ac.jp.

Extracellular matrix metalloproteinase inducer (EMMPRIN) participates in the breakdown of the extracellular matrix (ECM) by augmenting matrix metalloproteinase (MMP) expression. In the present study, we identified and characterized the menstrual cycle-dependent expression of EMMPRIN in human endometrium in vivo. At the proliferative phase of the menstrual cycle, EMMPRIN was detected in glandular epithelium of the basal layer in endometrium. In addition, at the superficial region of the functional layer, EMMPRIN was expressed in stroma but not glandular epithelium. At the secretory phase, EMMPRIN was found in both stroma and glandular epithelium of the functional layer and glandular epithelium of the basal layer. Furthermore, EMMPRIN colocalized with MMP-1/collagenase-1 in the glandular epithelium in vivo. Western blot analysis of tissue from the functional layer showed that EMMPRIN species with molecular weights of approximately 35 and 47 kDa were detected at the proliferative phase, whereas approximately 35- and 51-kDa EMMPRIN species were predominantly expressed at the secretory phase. In addition, the variant EMMPRIN molecules were found to differ in glycosylation. On the other hand, EMMPRIN was constitutively produced in primary cultured endometrial stromal and glandular epithelial cells. The production and glycosylation of EMMPRIN in the stromal cells were augmented by progesterone at the posttranscriptional and posttranslational stages, respectively. These results suggest for the first time that EMMPRIN is expressed in human endometrium during the menstrual cycle and that its expression and glycosylation are augmented by progesterone. Moreover, EMMPRIN may be involved in ECM breakdown at the interface between endometrial cells and ECM by using EMMPRIN-bound MMP-1.

This work was supported by the Bio-oriented Technology Research Advancement Institution.

Abbreviations: E2, 17ß-Estradiol; ECM, extracellular matrix; EMMPRIN, extracellular matrix metalloproteinase inducer; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3 phosphate dehydrogenase; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; P4, progesterone; PG, prostaglandin; TIMP, tissue inhibitor of metalloproteinases.

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