Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serpins encompass a superfamily of proteinase inhibitors that regulate many of the serine proteinases involved in inflammation and hemostasis. In vitro, many serpins are catalytically inactivated by proteinases that they do not inhibit, leading to the concept of proteolytic down-regulation of serpin inhibitory capacity. The extent to which down-regulation of serpin activity occurs in vivo is debated, since little is known of the rates at which the process occurs. To address this debate, we have measured the rates of inactivation of three serpins, alpha 1-proteinase inhibitor (alpha 1PI), alpha 1-antichymotrypsin (alpha 1ACT), and antithrombin III (ATIII), by three human matrix metalloproteinases (MMPs-1, -2, and -3) thought to be involved in tissue destruction and repair. Our object was to establish a working kinetic model which can be used to predict whether serpin inactivation by these proteinases is likely to occur in vivo. We determined the rates of inactivation of these three serpins by each of the MMPs and compared these to rates of inhibition of the MMPs by an endogenous inhibitor, alpha 2-macroglobulin. An equation designed to predict the extent of substrate hydrolyzed by an enzyme in the presence of an enzyme inhibitor gave the following predictions of the inactivation in vivo: (i) ATIII is unlikely to be inactivated by the MMPs. (ii) MMP-2 (72-kDa gelatinase/type IV collagenase) is unlikely to inactivate any of the three serpins. (iii) MMP-1 (tissue collagenase) will inactivate alpha 1PI and alpha 1ACT only when its concentration saturates that of its controlling inhibitors. (iv) MMP-3 (stromelysin) may inactivate small amounts of alpha 1PI and more significant amounts of alpha 1ACT, even in the presence of its controlling inhibitors. Any physiologic or pathologic inactivation of these serpins by these MMPs that occurs in vivo will probably be due to MMP-3, and will likely only take place in tissues and inflammatory loci where the concentration of MMP inhibitors is depressed.
 ...
PMID:Kinetics and physiologic relevance of the inactivation of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -2 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin). 165 20

The tissue localization and content of the proteolytic enzyme cathepsin G and its inhibitor alpha 1-antichymotrypsin were studied in the local host reaction to loosening of total hip-replacement prostheses in eleven patients and were compared with those in samples of non-inflammatory tissue from the synovial capsule obtained during arthroscopies of the knee. Immunostaining demonstrated cellular localization of cathepsin G in 71 per cent of monocyte or macrophage-like cells and in 46 per cent of fibroblast-like cells in the samples of interface tissue between the bone and the loose acetabular component obtained at the time of the total hip replacements, and in 59 and 42 per cent, respectively, in the samples of pseudocapsular tissue obtained at the same time, whereas the synovial lining cells in the samples of non-inflammatory tissue from the synovial capsule revealed only a slight immunoreactivity to cathepsin G. Cathepsin-G activity was also measured with synthetic succinyl-alanine-alanine-proline-phenylalanine-paranitroanilide as a substrate, the degradation of which was monitored spectrophotometrically. In accordance with results from immunohistochemical studies, cathepsin-G activity was found in the samples of interface tissue (31.6 international units per liter) and the samples of pseudocapsular tissue (15.5 international units per liter) obtained during the total hip replacements, whereas the level of cathepsin-G was low in the samples of non-inflammatory synovial capsular tissue (2.5 international units per liter). Cathepsin-G activity in the samples of pseudosynovial fluid obtained at the time of the total hip replacements was low (2.4 international units per liter), although immunoblot analysis showed marked immunoreactive cathepsin G in the samples of pseudosynovial fluid. This low activity of cathepsin G might be explained by the presence of alpha 1-antichymotrypsin, which was detected by laser nephlometric immunoassay and immunoblot analysis. These results demonstrate increased concentration of cathepsin G locally in the tissues around loose total hip-replacement prostheses. Because cathepsin G is not only able to act on extracellular matrix components (such as gelatin, proteoglycan, elastin, and laminin) at a physiological pH but also is able to activate collagenase, gelatinase, and stromelysin proenzymes, to inactivate tissue inhibitor of metalloproteinases, and to modulate tumor necrosis factor-alpha, it may play an important role in the degradation of periprosthetic connective tissue and in the lysis of bone around the implant, thus contributing to the loosening of prostheses.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cathepsin G and alpha 1-antichymotrypsin in the local host reaction to loosening of total hip prostheses. 782 51