Tissue Inhibitor of Metalloproteinases (TIMP-1) Stimulates the Secretion of Collagenase from Human Skin Fibroblasts

Clark, Ian M.; Powell, Liz; Cawston, Tim E.

doi:10.1006/bbrc.1994.2264

Cited by 32 publications

(21 citation statements)

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“…The TIMP-1-procathepsin L complex was reported to stimulate steroidogenesis of rat testis and ovary in vitro (61), but TIMP-1-deficient mice gave little evidence for regulation of steroidogenesis in vivo (62). TIMP-1 also stimulates fibroblasts to produce MMP-1 (63). Recent studies of Zhao et al (64) demonstrated TIMP-1 accumulates in the nuclei of human fibroblasts in a cell cycle-dependent manner (maximal at the S phase), suggestive of its participation in cell growth.…”

Section: Timps Are Multifunctional Proteinsmentioning

confidence: 99%

Matrix Metalloproteinases

Nagase¹,

Woessner²

1999

Journal of Biological Chemistry

3,813

2,840

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The timely breakdown of extracellular matrix (ECM) 1 is essential for embryonic development, morphogenesis, reproduction, and tissue resorption and remodeling. The matrix metalloproteinases (MMPs), also called matrixins, are thought to play a central role in these processes. The expression of most matrixins is transcriptionally regulated by growth factors, hormones, cytokines, and cellular transformation (1, 2). The proteolytic activities of MMPs are precisely controlled during activation from their precursors and inhibition by endogenous inhibitors, ␣-macroglobulins, and tissue inhibitors of metalloproteinases (TIMPs). Table I lists currently known vertebrate matrixins. In addition, non-vertebrate members have been identified in sea urchins (3), Caenorhabditis elegans (4), soybean (5), and Arabidopsis thaliana (6). Most of these MMPs are the subject of individual chapters in the Handbook of Proteolytic Enzymes (7). This minireview focuses on recent progress in regulation of matrixin activities and their biological and pathological implications. Domain Structure and FunctionAll matrixins are synthesized as prepro-enzymes and secreted as inactive pro-MMPs in most cases. The primary structures of 20 vertebrate matrixins comprise several domain motifs, as illustrated in Fig. 1; the domain composition for each MMP is listed in Table I.The propeptide domain (about 80 amino acids) has a conserved unique PRCG(V/N)PD sequence. The Cys within this sequence (the "cysteine switch") ligates the catalytic zinc to maintain the latency of pro-MMPs (8, 9). This sequence is missing in MMP-23 (10). Stromelysin 3 (MMP-11), MT-MMPs, Xenopus MMP, and MMP-23 have a proprotein processing sequence RX(K/R)R at the C-terminal end of the propeptide, and MMP-11 (11) and MMP-14 (12) were shown to be activated intracellularly by furin.The catalytic domain (about 170 amino acids) contains a zinc binding motif HEXXHXXGXXH and a conserved methionine, which forms a unique "Met-turn" structure (13). This domain consists of a five-stranded ␤-sheet, three ␣-helices, and bridging loops (14). These backbone structures including the "Met-turn" are similar to those of the members from other metalloproteinase families, i.e. astacins, reprolysins (ADAMs), and serralysins; these four families constitute the "metzincins" (13). The catalytic domains of matrixins have an additional structural zinc ion and 2-3 calcium ions, which are required for the stability and the expression of enzymic activity. MMP-2 and MMP-9 have three repeats of fibronectin-type II domain inserted in the catalytic domain. These repeats interact with collagens and gelatins (15, 16).The C-terminal hemopexin-like domain (about 210 amino acids) has an ellipsoidal disk shape with a four bladed ␤-propeller structure; each blade consists of four antiparallel ␤-strands and an ␣-helix (17). The hemopexin domain is an absolute requirement for collagenases to cleave triple helical interstitial collagens (18), although the catalytic domains alone retain proteolytic activity toward other substra...

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Section: Timps Are Multifunctional Proteinsmentioning

confidence: 99%

Matrix Metalloproteinases

Nagase¹,

Woessner²

1999

Journal of Biological Chemistry

3,813

2,840

View full text Add to dashboard Cite

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“…Interestingly, expression of this prototypical class of inhibitors does not correlate inversely with enhanced MMP activity in situ, as would be expected with increased matrix turnover (26,27). Additionally, certain TIMPs (e.g., TIMP-2) are implicated in the membrane-type metalloproteinase-mediated (MT-MMP-mediated) activation of distinct MMP family members (e.g., MMP-2 and MMP-13), as well as in the release of active MMPs (28,29). Thus, operation of inhibitory mechanisms beyond TIMPs has been postulated in atheroma, although simple quantitative correlation of MMP to TIMP probably does not adequately reflect complex in vivo situations (e.g., local concentrations of matrix-degrading enzymes and their inhibitors might vary due to compartmentalization; see refs [30][31][32].…”

Section: Tissue Factor Pathway Inhibitor-2 Is a Novel Inhibitor Of Mamentioning

confidence: 98%

Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis

Herman

Sukhova²,

Kisiel³

et al. 2001

J. Clin. Invest.

205

130

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Degradation of ECM, particularly interstitial collagen, promotes plaque instability, rendering atheroma prone to rupture. Previous studies implicated matrix metalloproteinases (MMPs) in these processes, suggesting that dysregulated MMP activity, probably due to imbalance with endogenous inhibitors, promotes complications of atherosclerosis. We report here that the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor. TFPI-2 diminished the ability of the interstitial collagenases MMP-1 and MMP-13 to degrade triple-helical collagen, the primary load-bearing molecule of the ECM within human atheroma. In addition, TFPI-2 also reduced the activity of the gelatinases MMP-2 and MMP-9. In contrast to the "classical" tissue inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with MMP levels in human atheroma. TFPI-2 colocalized primarily with smooth muscle cells in the normal media as well as the plaque's fibrous cap. Conversely, the macrophage-enriched shoulder region, the prototypical site of matrix degradation and plaque rupture, stained only weakly for TFPI-2 but intensely for gelatinases and interstitial collagenases. Evidently, human mononuclear phagocytes, an abundant source of MMPs within human atheroma, lost their ability to express this inhibitor during differentiation in vitro. These findings establish a new, anti-inflammatory function of TFPI-2 of potential pathophysiological significance for human diseases, including atherosclerosis.

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“…Recently, it was shown that TIMPs exert growth factor-like activities and may even promote extracellular matrix degradation. 11 The latter is supported by findings presented by Clark et al 12 and Roeb et al, 13 who demonstrated that cells incubated with TIMP expressed higher levels of MMP-1 12 or MMP-2, 13 indicating that the inhibitor not only inhibits enzyme activity but also promotes enzyme synthesis. If, under the influence of an inhibitor, cells indeed are stimulated to increase MMP activity, then this may explain the mixed findings reported on the use of synthetic MMP inhibitors.…”

mentioning

confidence: 60%

Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase‐2 (gelatinase A) without inhibiting its activation

Kerkvliet

Jansen

Schoenmaker

et al. 2003

Cancer

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BACKGROUNDIn the current study, the authors investigated the effects of synthetic low molecular weight inhibitors of matrix metalloproteinases (MMPs) on the expression and activation of MMP‐2 in a three‐dimensional tissue system.METHODSRabbit periosteal explants were cultured with or without various concentrations of the MMP inhibitors CT1166, CT1399, or CT1746, and conditioned media and tissue extracts were analyzed for the expression and activity of MMP‐2.RESULTSThe data showed that blocking the activity of all MMPs with relatively high inhibitor concentrations completely prevented the conversion of pro‐MMP‐2 into its active form and that the level of protein was decreased. Selective inhibition of the activity of gelatinases (MMP‐2 and MMP‐9) by using low inhibitor concentrations, however, induced a higher level of active MMP‐2 and increased its expression significantly.CONCLUSIONSThe current observations indicate that selective inhibitors of MMPs affect the expression and activity of MMP‐2, thus providing clues regarding the differing effects such inhibitors appear to have when applied in vivo. Cancer 2003;97:1582–88. © 2003 American Cancer Society.DOI 10.1002/cncr.11193

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Tissue Inhibitor of Metalloproteinases (TIMP-1) Stimulates the Secretion of Collagenase from Human Skin Fibroblasts

Cited by 32 publications

References 0 publications

Matrix Metalloproteinases

Matrix Metalloproteinases

Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis

Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase‐2 (gelatinase A) without inhibiting its activation

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