Regulation and restricted expression of interstitial collagenase suggest a pivotal role in the initiation of menstruation.

Collagenases are the only mammalian enzymes able to cleave, at neutral pH, the triple helical domain of fibrillar collagens, major constituents of the extracellular matrix of the endometrium. Interstitial collagenase is expressed, secreted and activated in human endometrium only just before and during menstruation. The expression of interstitial collagenase is restricted to the areas of the functional layer of the endometrium which are breaking down and to fragments which have been shed. In endometrial explants, combined sex steroids tightly control the expression, secretion and activation of interstitial collagenase, as well as the preservation of the extracellular matrix. These observations imply a pivotal role for this proteinase in the initiation of menstruation

[Collagenase and Related Matrix Metalloproteinases - a Prominent Role in the Initiation of Menstruation]

The human endometrium shows striking structural changes during the menstrual cycle. If no pregnancy develops, the fall of plasma progesterone and estradiol induces extracellular matrix degradation leading to haemorrhagia and mucosal shedding, i. e. menstruation. The mechanisms of endome trial tissue breakdown remain obscure. A major role of lysosomal hydrolases is not supported by biochemical evidence, whereas recent studies by several laboratories including our own suggest that interstitial collagenase and related matrix metalloproteinases (MMPs) are involved. We have demonstrated that human endometrium in tissue culture can produce interstitial collagenase and gelatinases A and B. Both the expression and the activation of these MMPs were inhibited by physiological concentrations of progesterone and estradiol. Moreover, in fresh human endometrial tissue, expression of mRNA, protein and activity of interstitial collagenase, as well as of mRNA of several other MMPs is limited to the perimenstrual period. In such tissues, immunolocalisation and in situ hybridization show that the expression is focal. The tight hormonal control as well as the restricted temporal and spatial expression of MMPs in human endometrium all point to a pivotal role of interstitial collagenase and other MMPs in the initiation of menstruation

Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases.

The mechanisms underlying the menstrual lysis leading to shedding of the human endometrium and its accompanying bleeding are still largely unknown. In particular, whether breakdown of the endometrial fibrillar extra-cellular matrix that precedes bleeding depends on aspartic-, cysteine-, serine-, or metalloproteinases remains unclear. In the present study, menstrual regression of the human endometrium was mimicked in organ culture. Whereas sex steroids could preserve tissue integrity only in nonperimenstrual explants, matrix breakdown upon sex steroid deprivation was completely and reversibly inhibited at all stages of the menstrual cycle by specific inhibitors of matrix metalloproteinases, but not by inhibitors of the other classes of proteinases. Matrix metalloproteinases are thus identified as the key class of proteinases involved in the initiation of menstruation

The expression of interstitial collagenase in human endometrium is controlled by progesterone and by oestradiol and is related to menstruation.

Human endometrial tissue, sampled at different periods of the reproductive cycle, expressed interstitial collagenase mRNA, protein and activity only just before and during the menstrual period. This clear-cut correlation and the inhibition of collagenase expression by progesterone and oestradiol in tissue culture point to a pivotal role of this proteinase in the mechanism of menstrual tissue breakdown and bleeding

Focal cellular origin and regulation of interstitial collagenase (matrix metalloproteinase-1) are related to menstrual breakdown in the human endometrium.

Recent studies suggest that interstitial collagenase (MMP-1) is an essential enzyme in the early events leading to menstruation. This study analyses its cellular origin, regulation and relation to extracellular matrix breakdown in the human endometrium, both in cultured and non-cultured samples. The source of MMP-1 was identified by in situ hybridization and by immunohistochemistry on serial sections. This was compared with the immunolocalization of other MMPs, steroid receptors, macrophages, and laminin. In non-cultured endometrium, MMP-1 was only expressed during the perimenstrual period. It was either restricted to superficial foci of stromal cells or extended towards the entire functional layer. MMP-1 expression remarkably correlated with matrix breakdown, as assessed by silver staining, and was prominent at the periphery of shedding fragments and along some arterioles. In cultured non-menstrual explants, MMP-1 expression was induced within two days after deprivation of sex steroids. Both in cultured and non-cultured samples, progesterone receptors were not detectable in epithelial cells at foci of MMP-1 expression. The same stromal cells could synthesize MMP-1, MMP-2 (gelatinase A) and MMP-3 (stromelysin-1), as well as laminin, and did not correspond to macrophages. In conclusion, MMP-1 is focally expressed in stromal cells of the functional layer of the endometrium, when and where steroid receptors disappear, and especially where tissue breakdown is prominent. These observations point to an essential role for MMP-1 in the early stages of menstruation

The matrix metalloproteinase-1 (MMP-1) expression in the human endometrium is inversely regulated by interleukin-1 alpha and sex steroids.

OBJECTIVE: To investigate the regulation of perimenstrual MMP-1 expression in human endometrium. DESIGN: In vitro study utilizing epithelial-stromal co-cultures. SETTING: Cell Biology Unit, International Institute of Cellular and Molecular Pathology, and Departments of Pathology and Gynecology, Saint-Luc University Clinics, Louvain University Medical School, Brussels, Belgium. METHODS: Contact-dependent and contact-independent co-cultures were established and resulting MMP-1 gene and protein expression was analyzed by RNase protection assays and soluble-collagen assays. RESULTS: MMP-1 expression in endometrial fibroblasts is markedly stimulated by epithelial cell-conditioned medium. This stimulation can be prevented by antibodies directed against interleukin 1 alpha (IL-1 alpha). Ovarian steroids inhibit MMP-1 production by IL-1 alpha-stimulated fibroblasts in vitro. CONCLUSION: Taken together, our results suggest that epithelium-derived IL-1 alpha is the most important paracrine induced of MMP-1 in endometrial fibroblasts. However, IL-1 alpha-stimulated MMP-1 production in the human endometrium is effectively blocked by ovarian steroids. We believe that this mechanism responsible for the MMP-1 repression that occurs when systemic sex steroid concentrations are high and the MMP-1 production and activity during the perimenstrual phase when estrogen and progesterone concentrations are low