Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy

The mammalian embryo cannot develop without the placenta. Its specialized cells (trophoblast, endoderm, and extraembryonic mesoderm) form early in development. They attach the embryo to the uterus (implantation) and form vascular connections necessary for nutrient transport. In addition, the placenta redirects maternal endocrine, immune, and metabolic functions to the embryo's advantage. These complex activities are sensitive to disruption, as shown by the high incidence of early embryonic mortality and pregnancy diseases in humans, as well as the numerous peri-implantation lethal mutations in mice. Integration of molecular and developmental approaches has recently produced insights into the molecules that control these processes.

https://science.sciencemag.org/content/sci/266/5190/1508.full.pdf

Implantation and the placenta: key pieces of the development puzzle

The matrix-degrading metalloproteinases are an intriguing family of enzymes that have evolved to digest specific extracellular matrix components. The expression of these enzymes is very highly regulated and can be controlled transcriptionally by a number of growth factors, tumor promoters, oncogenes, and hormones. It is suggested that the coordinated regulation of matrix metalloproteinases and their inhibitors by these agents modify the integrity of the extracellular matrix. These modifications may, at least in part, be responsible for mediating the effects of these factors on complex physiological processes.

The matrix-degrading metalloproteinases.

The implantation of fertilized ova and the formation of the placenta are crucial steps in reproduction. This review summarizes current information about these steps, including some of the molecular mechanisms that mediate them and how they may go awry, with consequent loss of the pregnancy.

Implantation and the survival of early pregnancy.

The specialized interaction between embryonic and maternal tissues is unique to mammalian development. This interaction begins with invasion of the uterus by the first differentiated embryonic cells, the trophoblasts, and culminates in formation of the placenta. The transient tumor-like behavior of cytotrophoblasts, which peaks early in pregnancy, is developmentally regulated. Likewise, in culture only early-gestation human cytotrophoblasts invade a basement membrane-like substrate. These invasive cells synthesize both metalloproteinases and urokinase-type plasminogen activator. Metalloproteinase inhibitors and a function-perturbing antibody specific for the 92-kD type IV collagen-degrading metalloproteinase completely inhibited cytotrophoblast invasion, whereas inhibitors of the plasminogen activator system had only a partial (20-40%) inhibitory effect. We conclude that the 92-kD type IV collagenase is critical for cytotrophoblast invasion.

/pdf/92-kd-type-iv-collagenase-mediates-invasion-of-human-2iekwfrxyq.pdf

92-kD type IV collagenase mediates invasion of human cytotrophoblasts.

In normal human pregnancy, invasion of the uterus and its arterial system by cytotrophoblasts extends through the entire decidua and the adjacent third of the myometrium. Our previous work showed that during the first trimester of pregnancy, invasion is accompanied by a marked change in the expression of cell adhesion molecules by invasive cytotrophoblasts. In the pregnancy disorder preeclampsia, cytotrophoblast invasion is limited to the superficial decidua, and few arterioles are breached. The purpose of this study was to determine whether cytotrophoblast expression of adhesion molecules in this disorder is also abnormal. Placental bed biopsy specimens from normal pregnancies and those complicated by preeclampsia were stained with anti-integrin antibodies. The results showed that adhesion molecule switching by invasive cytotrophoblasts is abnormal in preeclampsia, which suggests that this subpopulation of trophoblast cells fails to differentiate properly. A likely result is that the delicate balance of adhesive interactions that normally permit cytotrophoblast invasion is tipped in favor of those which restrain this process, with the net effect of shallow uterine invasion.

/pdf/preeclampsia-is-associated-with-abnormal-expression-of-2a4pal04i2.pdf

Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.

Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys

Purpose—To study choline metabolism in biopsies from non-enhancing Grade 2 (AS2) and Grade 3 (AS3) astrocytomas to determine whether (1) phosphocholine (PC) dominates in AS3, and (2) PC is associated with proliferation or angiogenesis. PC and glycerophosphocholine (GPC) are involved in phospholipid metabolism that accompanies mitosis. PC is the predominant peak in Grade 4 astrocytoma (GBM) while GPC dominates in AS2. Materials and Methods—We used high resolution magic angle spinning magnetic resonance spectroscopy to compare the concentrations of 10 metabolites in 41 biopsies (16 AS2 and 25 AS3) from 24 tumors. Immunohistochemistry was performed on paired biopsies to determine the cell density, Ki-67 proliferation index, and vascular endothelial growth factor (VEGF) angiogenic marker expression. Results—AS3 had higher PC than AS2; however, the PC:GPC was less than 1 in all cases irrespective of tumor grade. Within tumors, GPC increased with Ki-67 and PC and tCho increased with cell density. There was no association between any choline compound and VEGF. Conclusion—These data suggest that PC:GPC less than 1 is not unique to low grade glioma. Further, the PC concentration that is a marker of aggressive glial tumors is not tightly linked to cell proliferation or angiogenesis in non-enhancing astrocytomas.

/pdf/choline-metabolism-proliferation-and-angiogenesis-in-24szfo326t.pdf

Choline metabolism, proliferation, and angiogenesis in nonenhancing grades 2 and 3 astrocytoma.

In normal pregnancy human cytotrophoblast invasion of the uterus is the result of an unusual differentiation process in which polarized epithelial cells become detached from the chorionic villus basement membrane, aggregate into multilayered columns of nonpolarized cells, and rapidly penetrate the endometrium, the first third of the myometrium, and the associated spiral arterioles (1–4) (Fig. 7.1). The vascular component of the invasion process gives rise tophysiologic changes, a term used to describe the loss of the endothelial lining and most of the musculoelastic tissue of the spiral arteries, causing a striking increase in the caliber of these vessels (5). These changes occur in preparation for the dramatic increase in blood flow the fetus demands from the mother. The invasion process continues through the first trimester, peaks during the 12th week of pregnancy, and declines rapidly thereafter (1–4). The result is formation of the hemochorial placenta, in which the fetal trophoblast cells are constantly bathed by maternal blood.

King Chiu

Papers

92-kD type IV collagenase mediates invasion of human cytotrophoblasts.

Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.

Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys

Choline metabolism, proliferation, and angiogenesis in nonenhancing grades 2 and 3 astrocytoma.

Cytotrophoblast Expression of Integrin Extracellular Matrix Receptors Is Altered in Preeclampsia