The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity

Freise, Christian; Erben, Ulrike; Muche, Marion; Farndale, Richard W.; Zeitz, Martin; Somasundaram, Rajan; Ruehl, Martin

doi:10.1016/j.matbio.2009.08.001

Cited by 43 publications

(34 citation statements)

References 72 publications

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“…Because of chronic wounding, inflammation scar tissue accumulates. Its degradation is hampered by the overexpression of TIMPs and by the blockade of ECM-degrading activity via binding of latent MMPs to defined collagen structures, identified as the α2(VI) chain for collagenases [15] and, as reported here, fibrillar collagens for gelatinases. Thus, the ECM contributes to the availability and activity of its degrading enzymes by storing the inactive collagenase and gelatinase proforms.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, in the fibrosis resolution phase, MMP-2 activity in serum [18] and liver tissue [19] is high and high serum levels of MMP-9 and MMP-2 were found as early as 6 h after hepatectomy [20]. These observations pointed to a pool of ECM-stored MMPs as recently shown for collagenases [15]. …”

Section: Introductionmentioning

confidence: 93%

“…Recently, we established the α2 chain of collagen type VI as the main binding structure for sequestration of collagenases and stromelysin-1 proforms in fibrotic tissue [15]. Gelatinase binding sites were assumed to be within the rigid triple-helical collagen structure and thus far have been described only at the oligopeptide level [7,16].…”

Section: Introductionmentioning

confidence: 99%

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Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42

Ruehl

Muche

Freise

et al. 2011

Fibrogenesis Tissue Repair

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BackgroundFibrolytic and profibrotic activities of the matrix metalloproteinases (MMPs)-2 and -9 play a central role in liver fibrosis. Since binding to the extracellular matrix influences the activity of both gelatinases, here the role of fibrillar collagens as the most abundant matrix components in fibrotic tissue was investigated.ResultsIn situ zymography and immunohistology showed association of enzymatically inactive prodomain-containing proMMP-2 and proMMP-9 but not of their activated forms to fibrillar collagen structures, which are not substrates of these gelatinases. In solid-phase binding studies with human collagens and collagen fragments, up to 45% of [125I]-labeled proMMP-2 and proMMP-9 but not of active (act)MMP-2 and actMMP-9 were retained by natural collagenous molecules and by synthetic analogs containing repeated Gly-Pro-Hyp triplets (GPO). Surface plasmon resonance yielded binding constants for the interaction of collagen type I (CI) with proMMP-2 and proMMP-9 in a nanomolar range. Values for actMMP-2 and actMMP-9 were 30-40 times higher. Tenfold molar excesses of (GPO)10 reduced the interaction of CI with pro- and actMMP-2 by 22- or 380-fold and resulted in prodomain release accompanied by high enzymatic activation and activity. Pointing to gelatine substrate displacement, higher (GPO)10 concentrations blocked the enzymatic activity. The MMP-2 prodomain-derived collagen-binding domain peptide (P33-42) binds to the collagen-binding domain of MMP-2, thereby preserving enzymatic inactivity. Synthetic P33-42 peptide competed with proMMP-2 binding to CI and prevented (GPO)10-mediated proMMP-2 activation. In contrast to (GPO)10, P33-42 did not activate proMMP-2, making triple helical and hydroxyproline-containing (GPO)10 unique in modulating gelatinase availability and activity.ConclusionsThese findings suggest novel strategies using collagen analogs for the resolution of liver fibrosis via fibrotic matrix-sequestered gelatinases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42

Ruehl

Muche

Freise

et al. 2011

Fibrogenesis Tissue Repair

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“…As mentioned above, reactive nitrogen species can activate MMP-2 without proteolytic removal of the pro-domain. Furthermore, binding of various protein substrates to both MMP-2 and MMP-9 has been demonstrated to induce conformational changes that expose the active site without cleavage of the pro-domain (Bannikov et al 2002;Fedarko et al 2004;Jain et al 2008;Freise et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Tissue- and Cell-Specific Co-localization of Intracellular Gelatinolytic Activity and Matrix Metalloproteinase 2

Solli

Fadnes

Winberg

et al. 2013

J Histochem Cytochem.

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Matrix metalloproteinase 2 (MMP-2) is a proteolytic enzyme that degrades extracellular matrix proteins. Recent studies indicate that MMP-2 also has a role in intracellular proteolysis during various pathological conditions, such as ischemic injuries in heart and brain and in tumor growth. The present study was performed to map the distribution of intracellular MMP-2 activity in various mouse tissues and cells under physiological conditions. Samples from normal brain, heart, lung, liver, spleen, pancreas, kidney, adrenal gland, thyroid gland, gonads, oral mucosa, salivary glands, esophagus, intestines, and skin were subjected to high-resolution in situ gelatin zymography and immunohistochemical staining. In hepatocytes, cardiac myocytes, kidney tubuli cells, epithelial cells in the oral mucosa as well as in excretory ducts of salivary glands, and adrenal cortical cells, we found strong intracellular gelatinolytic activity that was significantly reduced by the metalloprotease inhibitor EDTA but not by the cysteine protease inhibitor E-64. Furthermore, the gelatinolytic activity was co-localized with MMP-2. Western blotting and electron microscopy combined with immunogold labeling revealed the presence of MMP-2 in different intracellular compartments of isolated hepatocytes. Our results indicate that MMP-2 takes part in intracellular proteolysis in specific tissues and cells during physiological conditions.

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“…In previous studies, we identified the α2 chain of collagen type VI as the main binding structure for sequestration of collagenases and stromelysin-1 proforms in fibrotic tissue [16], and showed that gelatinase binding sites are located on fibrillar collagen structures and the synthetic collagen analogue (Gly-Pro-Hyp) 10 ((GPO) 10 ) [17]. Using (GPO) 10 as a binding competitor for the interaction of the gelatinase proMMP-2 with collagen, a dissociation of the proMMP-2 prodomain accompanied by high enzymatic activation of MMP-2 could be achieved [17].…”

Section: Introductionmentioning

confidence: 99%

The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)₁₀promotes enzymatic activity of matrixmetalloproteinase-2in vitro

Freise

Ruehl²,

Erben³

et al. 2012

European Journal of Microbiology and Immunology

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Diseases such as liver fibrosis and intestinal inflammation are characterized by accumulated components of the extracellular matrix (ECM). Given that fibrillar collagen structures were shown to serve as storage site for inactive proforms of matrixmetalloproteinases (MMPs), modulating this MMP-collagen interaction might offer a rational interventional (therapeutic) approach to enhance degradation of accumulated ECM. The synthetic triple helical collagen analogue (Gly-Pro-Hyp) 10 -(GPO) 10 -was shown to trigger release and enzymatic activation of collagen sequestered proMMP-2. In the presented study, we, for the first time, investigated how MMP-(GPO) 10 interaction impacts cellular responses in vitro. We found that recombinant proMMP-2 induced proliferation of hepatic stellate cells (HSC), which was enhanced after addition of (GPO) 10 reaching comparable levels following incubation with fully activated MMP-2. In addition, (GPO) 10 induced HSC migration similar to the platelet-derived growth factor subunit-B. Further, the MMP-2-dependent invasion of HT1080 fibrosarcoma cells through an ECM membrane was enhanced after addition of (GPO) 10 . Since cellular proliferation and migration concomitant with matrix degradation is stimulated, we conclude that the MMP-(GPO) 10 interaction also functions in a physiological environment. Thus, a potential therapeutic effect of (GPO) 10 should be further tested in animal models for MMP-associated diseases such as colitis or fibrosis.

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The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity

Cited by 43 publications

References 72 publications

Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42

Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42

Tissue- and Cell-Specific Co-localization of Intracellular Gelatinolytic Activity and Matrix Metalloproteinase 2

The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)₁₀promotes enzymatic activity of matrixmetalloproteinase-2in vitro

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The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity

Cited by 43 publications

References 72 publications

Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42

Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42

Tissue- and Cell-Specific Co-localization of Intracellular Gelatinolytic Activity and Matrix Metalloproteinase 2

The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)10promotes enzymatic activity of matrixmetalloproteinase-2in vitro

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The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)₁₀promotes enzymatic activity of matrixmetalloproteinase-2in vitro