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

Authors

  • Erika H. M. Kerkvliet Ph.D.,

    1. Department of Periodontology, Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, The Netherlands
    2. Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands
    Search for more papers by this author
  • Ineke D. C. Jansen M.Sc.,

    1. Department of Periodontology, Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, The Netherlands
    Search for more papers by this author
  • Ton A. M. Schoenmaker B.Sc.,

    1. Department of Periodontology, Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, The Netherlands
    Search for more papers by this author
  • Andy J. P. Docherty Ph.D.,

    1. Celltech R & D, Slough, United Kingdom
    Search for more papers by this author
  • Wollter Beertsen D.D.S., Ph.D.,

    1. Department of Periodontology, Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, The Netherlands
    Search for more papers by this author
  • Vincent Everts Ph.D.

    Corresponding author
    1. Department of Periodontology, Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, The Netherlands
    2. Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands
    • Academic Medical Center, Department of Cell Biology and Histology, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
    Search for more papers by this author
    • Fax: 011 (31) 20697 4156


Abstract

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

Ancillary