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Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase‐2 (gelatinase A) without inhibiting its activation
Author(s) -
Kerkvliet Erika H. M.,
Jansen Ineke D. C.,
Schoenmaker Ton A. M.,
Docherty Andy J. P.,
Beertsen Wollter,
Everts Vincent
Publication year - 2003
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.11193
Subject(s) - matrix metalloproteinase , gelatinases , gelatinase a , gelatinase , matrix metalloproteinase inhibitor , in vivo , matrix (chemical analysis) , pharmacology , medicine , microbiology and biotechnology , biochemistry , cancer research , chemistry , biology , chromatography
BACKGROUND In 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. METHODS Rabbit 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. RESULTS The 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. CONCLUSIONS The 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