Origine cellulaire et régulation de la collagénase (MMP-1) dans l'endomètre humain eutopique et ectopique

Throughout the reproductive years, the human endometrium composed of a stromal and an epithelial compartment shows striking structural changes during the menstrual cycle. If no pregnancy develops, the fall of plasma oestradiom and progesterone concentrations induces, about every 28 days, a rapid and extensive focal lysis of the extracellular matrix argyrophilic fibrillar network and a collapse of the endometrial stroma. This leads to hemorrhages and mucosal shedding, i. e. menstruation. The menstrual tissue regression can be reproduced in vitro by the culture of human endometrial explants in the absence of added ovarian steroids. In such conditions, the preservation of the argyrophilic fibrillar network by specific inhibitors of matrix metalloproteinases (MMPs) demonstrates that enzymes of this family are involved in the degradation of the endometrial extracellular matrix. Furthermore, the inhibition by ovarian steroids of the expression, the secretion and the activation of several MMPs also preserves the tissue integrity of endometrial explants. Among MMPs, collagenases are the only mammalian proteinases able to cleave, at neutral pH, the triple helical domain of fibrillar collagens, major constituents of the endometrial extracellular matrix. In the human endometrium, interstitial collagenase (MMP-1) is only expressed, secreted and activated just before and during menstruation. The expression of MMP-1 is restricted to stromal foci of the functional layer of the endometrium, when and where progesterone receptors disappear, and especially where tissue breakdown is prominent. Moreover, the preferential expression of MMP-1, probably in concert with other MMPs, is thus presumably involved in the initiation of menstruation. Similarly, MMP-1, which is only expressed in foci of active endometriosis, could also be involved in tissue remodelling and bleeding, and possibly in the secondary shedding and reimplantation of these endometriotic lesionsL’endomètre, ou muqueuse utérine, est constitué d’un compartiment stromal et d’un épithélium glandulaire. Entre la ménarche et la ménopause, c’est un tissu jeune, que se renouvelle environ tous les 28 jours, après chaque menstruation. La menstruation, caractérisée par l’élimination vaginale de fragments d’endomètre et de sang, résulte de la chute prémenstruelle des concentrations plasmatiques d’œstradiol et de progestérone, suivie de la lyse focale de la trame réticulinique de la matrice extracellulaire et d’un collapsus du stromal endométrial. La régression menstruelle peut être reproduite in vitro par la culture d’explants d’endomètre humain en l’absence des stéroïdes ovariens. Dans ces conditions, la protection de la trame réticulinique par des inhibiteurs spécifiques des métalloprotéases matricielles (MMPs) démontre que des enzymes de cette famille sont responsables de la dégradation des fibres de la matrice extracellulaire endométriale. Par ailleurs, l’inhibition de l’expression, de la sécrétion et de l’activation de plusieurs MMPs par les stéroïdes ovariens, préserve aussi l’intégrité des explants endométriaux. Parmi les MMPs, les collagènes sont les seules enzymes capables de cliver à pH neutre la triple hélice des collagènes fibrillaires, constituants majeurs de la matrice extracellulaire endométriale. Dans l’endomètre humain, la collagénase interstitielle (MMP-1) n’est exprimée, sécrétée et activée que juste avant et pendant la menstruation. L’expression de la MMP-1 est limitée à des foyers de cellules stromales de la couche fonctionnelle de l’endomètre, là où les récepteurs de la progestérone ont disparu, et où la lyse tissulaire est évidente. De plus, l’expression de la MMP-1 en périphérie des artérioles spiralée et des petits vaisseaux sanguins suggère qu’elle pourrait être responsable d’hémorragies focales. Tous ces arguments plaident en faveur d’une intervention de la MMP-1 et de MMPs apparentées dans le déclenchement des règles. De même, la MMP-1 n’est exprimée que dans les foyers d’endométriose active, où elle pourrait également participer eu remodelage tissulaire et aux saignements de ces foyers, ainsi qu’à leur détachement secondaire et leur réimplantationThèse de doctorat en sciences biomédicales (biologie cellulaire) -- UCL, 199

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

Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions

Objective: To determine whether interstitial collagenase (matrix metalloproteinase-1), known to play a pivotal role in the initiation of menstruation, contributes to the pathogenesis of endometriosis. Design: Serial sections of peritoneal red and black endometriotic lesions, ovarian endometriotic cysts, and rectovaginal adenomyotic nodules were analyzed by in situ hybridization for the expression of matrix metalloproteinase-1 by silver staining for the integrity of the fibrillar extracellular matrix and by immunolabeling for the abundance of sex steroid receptors. Setting: Academic hospital and research laboratory. Patient(s): Premenopausal women undergoing laparoscopy for endometriosis. Intervention(s): Biopsy of endometriotic lesions, combined with endometrium whenever possible. Main Outcome Measure(s): Expression of matrix metalloproteinase-1 messenger RNA (mRNA). Result(s): Matrix metalloproteinase-1 mRNA was expressed focally in red peritoneal and ovarian endometriosis irrespective of the phase of the menstrual cycle but was not detectable in black peritoneal and rectovaginal lesions. Foci of matrix metalloproteinase-1 expression closely correlated with matrix breakdown and with the absence of P receptors in adjacent epithelial cells. Conclusion(s): Correlation of matrix metalloproteinase-1 expression with activity of endometriotic tissue suggests its involvement in tissue remodeling and bleeding, and possibly in the secondary shedding and reimplantation of endometriotic lesions

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