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J. Biol. Chem., Vol. 277, Issue 30, 27319-27327, July 26, 2002
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From the Division of Plastic and Reconstructive Surgery, Department
of Surgery, The Keck School of Medicine, University of Southern
California, Los Angeles, California 90033
The proteolytic activation of pro-matrix
metalloproteinase (MMP)-9 by conversion of the 92-kDa precursor into an
82-kDa active form has been observed in chronic wounds, tumor
metastasis, and many inflammation-associated diseases, yet the
mechanistic pathway to control this process has not been identified. In
this report, we show that the massive expression and activation of
MMP-9 in skin tissue from patients with chronically unhealed wounds
could be reconstituted in vitro with cultured normal human
skin by stimulation with transforming growth factor-
Tumor Necrosis Factor-
-induced Proteolytic Activation
of Pro-matrix Metalloproteinase-9 by Human Skin Is Controlled
by Down-regulating Tissue Inhibitor of Metalloproteinase-1 and Mediated
by Tissue-associated Chymotrypsin-like Proteinase*
,
and
tumor necrosis factor (TNF)-
. We dissected the mechanistic pathway
for TNF- induced activation of pro-MMP-9 in human skin. We found
that proteolytic activation of pro-MMP-9 was mediated by a
tissue-associated chymotrypsin-like proteinase, designated here as
pro-MMP-9 activator (pM9A). This unidentified activator specifically
converted pro-MMP-9 but not pro-MMP-2, another member of the gelatinase
family. The tissue-bound pM9A was steadily expressed and not regulated
by TNF-, which indicated that the cytokine-mediated activation of
pro-MMP-9 might be regulated at the inhibitor level. Indeed, the skin
constantly secreted tissue inhibitor of metalloproteinase-1 at the
basal state. TNF-, but not transforming growth factor-,
down-regulated this inhibitor. The TNF--mediated activation of
pro-MMP-9 was tightly associated with down-regulation of tissue
inhibitor of metalloproteinase-1 in a dose-dependent
manner. To establish this linkage, we demonstrate that the recombinant
tissue inhibitor of metalloproteinase-1 could block the activation of
pro-MMP-9 by either the intact skin or skin fractions. Thus, these
studies suggest a novel regulation for the proteolytic activation of
MMP-9 in human tissue, which is mediated by tissue-bound activator and controlled by down-regulation of a specific inhibitor.
*
This work was supported in part by the Plastic Surgery
Education Society and the Wound Healing Foundation (to Y. P. H.) and National Institutes of Health Grant GM 50967 (to W. L. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: 1450 San Pablo St.,
Suite 2000, Division of Plastic and Reconstructive Surgery, Los
Angeles, CA 90033. Tel.: 323-442-3856; Fax: 323-442-6477; E-mail:
yhan@surgery.usc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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