EMMPRIN Regulates Tissue Remodeling in the Endometrium

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Endometriosis is defined as the presence of endometrial glands and stroma at ectopic sites, most commonly on the peritoneum within the pelvic cavity. The incidence of endometriosis is estimated to range from 30- 60% in women with pelvic pain and infertility and the associated health care costs are enormous. Implantation of endometrial fragments at ectopic sites is thought to be regulated by cytokines and growth factors secreted locally by immune cells as well as by the endometrial cells themselves. The infertility that is often associated with endometriosis is due, at least in part, to alterations in gene expression in the eutopic endometrium. These altered patterns of gene expression result in an endometrial environment that is not receptive to the implanting embryo and cannot sustain its development. We have shown that a glycosylated, trans-membrane protein called Extra-Cellular Matrix Metalloproteinase Inducer (EMMPRIN) is expressed in both the human and mouse uterus and regulates production of metalloproteinases by uterine stromal cells. EMMPRIN expression is upregulated in eutopic as well as ectopic endometrium of women and baboons with endometriosis. Using a mouse EMMPRIN knockout model we have shown that in mice lacking EMMPRIN expression, uterine stromal cells experience premature decidualization in response to oil injection and are infertile. Treatment of cultured uterine stromal cells with EMMPRIN inhibits expression of decidualization markers such as alkaline phosphatase-2 and induces expression of several cytokines and chemokines by these cells. Thus it appears that EMMPRIN is a multi-functional regulator of endometrial remodeling. Our specific aims are; #1: To determine how secretion of full-length, soluble EMMPRIN by uterine epithelial cells is regulated and how EMMPRIN regulates production of cytokines, chemokines and angiogenic factors by uterine stromal cells. #2: To determine how EMMPRIN regulates proliferation and decidualization of uterine stromal cells and to clarify the intra-cellular signaling pathway used by EMMPRIN in these cells. #3: To determine the effects of EMMPRIN on epithelial-to-mesenchymal transition of mesothelial cells. The proposed studies will clarify the role of EMMPRIN in invasion of endometrial fragments through the mesothelium leading to establishment of endometriotic lesions. They will also help to explain why aberrant expression of EMMPRIN in eutopic endometrium could result in failure of implantation.