Ghislain Opdenakker talks
with ScienceWatch.com and answers a few questions
about this month's New Hot Paper in the field of
Pharmacology & Toxicology.
Article Title: Matrix metalloproteinase inhibitors
as therapy for inflammatory and vascular
Authors: Hu, JL;Van den Steen, PE;Sang,
Journal: NAT REV DRUG DISCOV
Year: JUN 2007
* Catholic Univ Louvain, Rega Inst Med Res,
Minderbroedersstr 10, B-3000 Louvain, Belgium.
* Catholic Univ Louvain, Rega Inst Med Res, B-3000 Louvain,
(addresses have been truncated)
Why do you think your paper is highly
This review challenges a number of prevailing views on matrix
metalloproteinases (MMPs), brings together an enormous amount of
information in a critical way, and has an important positive message for
the future development of matrix metalloproteinase inhibitors (MMPIs). For
instance, we challenge the views that MMPIs' primary disease targets should
be invasive or metastatic cancer or that broad-spectrum MMPIs will have any
benefit for long-term therapy (of cancer and chronic diseases). By now, it
is clear that MMPs are key players in inflammatory and vascular diseases,
which constitute much better targets than cancer.
Cancers are genetically unstable, and thus less predictable, whereas, in
inflammatory and vascular diseases, the genetics of all tissues are normal,
the predictions will be simpler and the readouts will be clearer for
chronic inflammation and vascular disease models.
Another mistake from the past, namely oversimplification, should be
avoided. By now, we know that MMPs have many substrates in physiology and
pathology and that specific MMPs are constitutive, whereas others are
induced, for instance, during infections or inflammation. The latter ones
are ideal targets for the development of highly specific inhibitors,
whereas the inhibition of constitutive MMPs will certainly lead to side
"One dream is to one day have the
crystallographic picture of full-size human
MMP-9. This project must be doable in
collaboration with other experts and the
future picture will tell us more than a
Another point of view is that we are in favor of and contemplate the
short-term use of MMPIs for acute and life-threatening diseases, rather
than long-term use. Maybe this is less attractive for commercial
developments, but we give sufficient examples in the review that should
stimulate this research.
Finally, we have invested an enormous amount of energy and critical
thinking to summarize the literature on MMP knockout mice and MMPI studies.
Stimulating the thinking that many currently available knockout mice are in
fact leaky (thus not really knockout), that the essence of science is in
confirmation, comparison, and complementation, that not the factual results
but the interpretations which we give to in vivo results may often
be wrong; these are all essential contributions of this article.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The article has several layers of information. It gives a synthesis of
knowledge on MMPIs and MMP knockout studies. It describes a number of new
views and insights as to why previous MMPI studies failed and, at the same
time, outlines many opportunities for how the money invested in excellent
academic and pharmaceutical research on MMPIs may bring enormous returns to
patients, medical professionals, and society.
The synthesis of the present knowledge of MMPIs was considerably enhanced
thanks to the insights, critical appraisal, and eye for details by the
group of medicinal chemists of Professor Qing-Xiang Amy Sang at Florida
State University, USA. In this way, the work is a truly transcontinental
effort. This was further enhanced with the help by the staff of
Nature Publishing Group.
One trigger to write this review was to further enhance the work of our
postdoctoral fellows. Dr. Jialiang Hu developed a new high throughput
methodology for screening MMPIs and, by using this, was able to simulate
evolution in the test tube and to discover a novel peptide inhibitor for
MMP-9 with which we could block the acute lethality of endotoxin shock in
These findings are quite stimulating, particularly in view of the fact that
currently, about half of the patients with severe sepsis or shock
syndromes, even in our modern hospitals, may not survive their stay in the
intensive care unit. The use of MMPIs in sepsis syndromes really needs to
be carefully examined.
More than a decade ago, Dr. Liesbet Paemen developed another method for
screening and discovered that tetracyclines are MMPIs. In addition, we used
her method with success to make the first inhibitory monoclonal antibodies
against MMP-9. These antibodies are still today the most selective
inhibitors against human MMP-9.
Last but not least, to define MMPIs one needs the enzyme—lots of the
enzyme. In fact, together with Dr. Stefan Masure and Dr. Philippe Van den
Steen, our group has always invested a lot in the production of the enzyme
MMP-9. For years, we used buffy coat neutrophils from thousands of blood
donations to produce natural MMP-9. Afterwards, we added a recombinant
production line. This gave us the additional opportunities to study domain
and point mutants of the protein.
In conclusion, scientists from three continents have integrated their work
and ideas in the present scientific literature with the hope being of
stimulating future developments.
Would you summarize the significance of your paper
in layman's terms?
Drugs that have been developed and still can be improved for the treatment
of cancer, may be much better developed for the treatment of acute
inflammatory (for instance meningitis, sepsis, acute exacerbations of
arthritis, and multiple sclerosis) and acute vascular—for instance,
How did you become involved in this research, and
were there any problems along the way?
In 1954, Piet De Somer founded The Rega Institute for Medical Research,
which has established a great tradition in translational research, in
particular, in virology and immunology. De Somer's younger mentors, Alfons
Billiau, Erik De Clercq, Hendrik Eyssen, and Michel Vandeputte, each
maintained an open mind towards innovation and excellence and are quite
My doctoral work was already on a proteinase: the well-known serine
proteinase t-PA. During my postdoc at Yale University with Peter Lengyel, I
refined my knowledge and practical skills on the interactions of cytokines
and proteinases. After my return to the University of Leuven in 1987, I
started working on MMPs and quickly chose to concentrate on MMP-9, alias
gelatinase B, because this enzyme was exquisitely induced and regulated by
inflammatory cytokines and chemokines.
This educated choice was a really good one: from the present approximately
20,000 PubMed entries on all MMPs together, about half are on MMP-9.
Together with a great colleague and friend, Jo Van Damme, I had the
opportunity to create an environment that is challenging and complementary
in terms of technology (molecular versus cellular versus in vivo)
and in topics (cytokines, chemokines, and proteinases). In doing so, we
kept a focus on inflammation research.
It would be incorrect to say that I have never encountered problems in my
research, but these problems are sublimated by the friendship of
collaborators, both locally and in top institutes abroad, from Oxford to
Heidelberg, and from Dublin to Rehovot.
Where do you see your research leading in the
MMP and MMPI research is not different from any other topic; we try to dig
further and deeper and, to achieve this, one needs to bring together
expertise from many disciplines. One dream is to one day have the
crystallographic picture of full-size human MMP-9. This project must be
doable in collaboration with other experts and the future picture will tell
us more than a thousand words.
Another project is the definition of the spectrum of intracellular MMP-9
substrates. We know a number of important secreted extracellular substrates
quite well and have recently listed all known membrane-associated
substrates, whereas colleagues abroad are using state-of-the-art proteomics
technology to define the repertoire of all extracellular substrates.
However, MMP-9 as an inflammatory enzyme must have many substrates from
inside cells. Whether and how this enzyme contributes to cleavage of
molecules that are released when cells die and how this might contribute to
the origin or development of diseases are key questions which keep us busy.
In return, solving these questions by using a multidisciplinary approach
might give new momentum to MMPI research.
Using recombinant MMP-9 domain mutants, we hope to be able to understand
how monomers and oligomers interact with substrates, in other words to
understand molecular complex formation, also because this knowledge will
give insights on how to develop new types of MMPIs for specific
pathologies. Posttranslational modifications of MMPs are also
insufficiently understood in terms of functions and potentials for
Thanks to the support by Prof. Raymond Dwek and Prof. Pauline Rudd, MMP-9
has become a model molecule for glycobiology research, a discipline with a
great future. In a collaboration with Prof. Bernd Arnold from the German
Cancer Research Center, we developed, 10 years ago, two lines of MMP-9
knockout mice with brown fur: one leaky MMP-9-deficient line, and one
nonleaky real knockout line.
Because of subfertility problems in the latter mice, it took us 10 years of
patience and a bit of good luck to backcross the knockouts to C57BL/7 for
13 generations in order to obtain, in the end, black MMP-9 knockout mice.
Only now can we think of animal model experiments that will hopefully show
the real role of MMP-9 in health and diseases.
Meanwhile, we remain convinced that perhaps the simplest way to generate a
highly selective MMP-9 inhibitor is by hybridoma technology. We have
successfully made such inhibitory monoclonal antibodies against human and
mouse MMP-9. If, one day, patients will be helped with such monoclonals or
derivatives, all our efforts will have been worthwhile.
Do you foresee any social or political implications
for your research?
In the 1980s, we started molecular biology research at the University of
Leuven and transferred technology to many Belgian scientists in this
discipline. In the 1990s, research on MMPs was superimposed on our cytokine
and chemokine gene cloning work and the MMPI project was started. In
addition to the start of an amplification effect, I can now count 10
postdocs as Rega Institute alumni. They each successfully continue to work
in inflammation research at universities or governmental and pharmaceutical
In 1995, we discovered that tetracyclines (e.g., minocycline) inhibit MMP-9
and might be useful for the treatment of inflammatory and vascular
diseases. Tetracyclines are inexpensive drugs with a high therapeutic
index. It is gratifying to see that, on the basis of our studies, several
clinical trials have shown the beneficial effects of tetracyclines for the
treatment of multiple sclerosis (MS). In 2003, Dr. Inge Nelissen from our
laboratory described that recombinant beta-interferon (used for the
treatment of multiple sclerosis) is degraded by MMP-9, which is exactly the
enzyme that is induced in the central nervous system of the patients
suffering from MS.
As a medical professional, and being concerned about the health of
individual patients and also about the societal costs of healthcare, I have
been trying on many occasions to advocate the combined use of tetracyclines
and beta-interferon for treatment of MS: most probably this will reduce
many observed side effects of monotherapy with interferon and,
intrinsically, this will be much less expensive.
I foresee that one day our science policymakers will have enough vision and
courage to sponsor double-blind clinical trials of such combination
therapies of beta-interferon with tetracyclines or other MMPIs versus
monotherapy and that the industrial managers will have the insight that it
is possible to reduce therapy costs with presently available drug
combinations, while improving the quality of life of the patients.
Ghislain Opdenakker, M.D., Ph.D.
Professor of Immunology
Head of the Department of Microbiology and Immunology
Leuven University Medical School
Rega Institute for Medical Research
Leuven, Belgium Web | See Also
Keywords: matrix metalloproteinases, inflammatory and vascular
diseases, sepsis syndromes, inhibitory monoclonal antibodies,
interactions of cytokines and proteinases, inflammatory cytokines and
chemokines, extracellular substratesO.