Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetracyclines are potent inhibitors of 2 major matrix metalloproteinases which have been implicated in connective tissue degradation: collagenase and Type IV collagenase/gelatinase. We directly identified these enzyme activities in extracts of inflamed paw tissue from rats with adjuvant arthritis. Oral tetracycline therapy suppressed metalloproteinase activity in arthritic tissue, but even very high doses failed to exhibit substantial antiinflammatory efficacy (reduced joint swelling and paw diameter). Flurbiprofen, a conventional nonsteroidal antiinflammatory drug, reduced inflammatory indices as expected. The combination of the 2 agents administered orally completely inhibited collagenase activity, significantly inhibited gelatinase activity and produced substantial normalization of radiographic joint damage, far greater than either drug alone. Tetracycline inhibition curves in vitro suggest that the collagenase in this tissue is not of fibroblast origin. Tetracycline derivatives might be useful adjuncts to prevention of tissue damage in chronic inflammatory arthritides.
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PMID:Tetracyclines suppress matrix metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorate bone damage. 140 31

Pig articular cartilage, overlaid with a minced preparation of synovium from the same joint, underwent extensive matrix degradation during a two-week culture period. This degradation was associated with de novo synthesis by the synovium of specific neutral proteoglycan- and collagen-degrading enzymes. Both enzymes exhibited neutral pH optima, and were inhibited by serum and the metal ion chelators EGTA and 1,10-phenanthroline. The neutral proteoglycanase cleaved the core protein of isolated proteoglycan. The effects of some anti-inflammatory drugs on synovial enzyme production and cartilage metabolism were investigated. The steroids, dexamethasone and prednisolone, inhibited production of both enzymes whereas the non-steroidal anti-inflammatory drugs (NSAID's), flurbiprofen and indomethacin, slightly increased medium enzyme levels. Flurbiprofen and indomethacin had no effect on the extent of synovium-mediated cartilage degradation as assessed histologically. Inhibition by the steroids of synovial collagenase production correlated with inhibition of cartilage collagen breakdown, whereas inhibition of synovial proteoglycanase production did not prevent extensive proteoglycan breakdown. Experiments using radiotracer techniques indicated that dexamethasone, whilst partially inhibiting synovium-mediated proteoglycan degradation, severely inhibited cartilage proteoglycan synthesis thus resulting in net proteoglycan loss.
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PMID:Studies on the release of proteolytic enzymes during synovium-induced cartilage breakdown in vitro and the actions of anti-inflammatory drugs. 632 20

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to inhibit prostaglandin synthetic enzyme, cyclooxygenases (COXs), as well as to exhibit anti-tumor activity although at much higher concentrations. 15-Hydroxyprostaglandin dehyrogenase (15-PGDH), a key prostaglandin catabolic enzyme, was recently shown to be a tumor suppressor. Effects of NSAIDs on 15-PGDH expression were therefore examined. Flurbiprofen and several other NSAIDs were found to induce 15-PGDH expression in human colon cancer HT29 cells. Flurbiprofen, the most active one, was also shown to induce 15-PGDH expression in other types of cancer cells. Induction of 15-PGDH expression appeared to occur at the stage of mRNA as levels of 15-PGDH mRNA were increased by flurbiprofen in HT29 cells. Levels of 15-PGDH were also found to be regulated at the stage of protein turnover. MEK inhibitors, PD98059 and U-0126, which inhibited ERK phosphorylation were shown to elevate 15-PGDH levels very significantly. These inhibitors did not appear to alter 15-PGDH mRNA levels but down-regulate matrix metalloproteinase-9 (MMP-9). This protease was shown to degrade and inactivate 15-PGDH suggesting that elevation of 15-PGDH levels could be due to inhibition of MMP-9 expression by these inhibitors. Similarly, flurbiprofen was also demonstrated to inhibit ERK activation and to down-regulate MMP-9 expression. Furthermore, flurbiprofen was shown to induce the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9. The turnover of 15-PGDH was found to prolong in the presence of flurbiprofen as compared to that in the absence of this drug. Taken together, these results indicate that flurbiprofen up-regulates 15-PGDH by increasing the expression and decreasing the degradation of 15-PGDH in HT29 cells.
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PMID:15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer HT29 cells. 1950 Oct 39

NSAIDs are known to be inhibitors of cyclooxygenase-2 (COX-2) accounting for their anti-inflammatory and anti-tumor activities. However, the anti-tumor activity cannot be totally attributed to their COX-2 inhibitory activity as these drugs can also inhibit the growth and tumor formation of COX-2-null cell lines. Several potential targets aside from COX-2 for NSAIDs have been proposed. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH), a key prostaglandin catabolic enzyme, was recently shown to be a tumor suppressor. Effects of NSAIDs on 15-PGDH expression were therefore studied. Flurbiprofen, indomethacin and other NSAIDs stimulated 15-PGDH activity in colon cancer HT29 cells as well as in lung cancer A549 cells and glioblastoma T98G cells. (R)-flurbiprofen and sulindac sulfone, COX-2 inactive analogs, also stimulated 15-PGDH activity indicating induction of 15-PGDH is independent of COX-2 inhibition. Stimulation of 15-PGDH expression and activity by NSAIDs was examined in detail in colon cancer HT29 cells using flurbiprofen as a stimulant. Flurbiprofen stimulated 15-PGDH expression and activity by increasing transcription and translation and by decreasing the turnover of 15-PGDH. Mechanism of stimulation of 15-PGDH expression is not clear. Protease(s) involved in the turnover of 15-PGDH remains to be identified. However, flurbiprofen down-regulated matrix metalloproteinase-9 (MMP-9) which was shown to degrade 15-PGDH, but up-regulated tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9 contributing further to a slower turnover of 15-PGDH. Taken together, NSAIDs may up-regulate 15-PGDH by increasing the protein expression as well as decreasing the turnover of 15-PGDH in cancer cells.
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PMID:Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs). 2176 48