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Matrix metalloproteinase inhibitors in the treatment of arthritiscomment on the article by vincenti et al.

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Number 4, April 1995, pp 574576
0 1995, American College of Rheumatology
Matrix metalloproteinase inhibitors in the treatment of
arthritis: comment on the article by Vincenti et a1
To the Editor:
Vincenti et a1 have provided a well-written and
balanced review of the potential applicability of matrix
metalloproteinase (MMP) inhibitors for the treatment of
osteoarthritis and/or rheumatoid arthritis (1). A few comments may be of interest.
First, I would suggest that the question mark at the
end of their subtitle (“Easier Said Than Done?”) should
clearly be an exclamation mark-there is little doubt that
applying the basic science of MMP inhibition to clinical
practice will be a task fraught with difficulty. At a recent
conference on this subject (Inhibition of Matrix Metalloproteinases: Therapeutic Potential; Tampa FL, January, 1994,
sponsored by the New York Academy of Sciences and Long
Island Jewish Medical Center), it was the consensus that
selecting a suitable patient population, study time frame,
and set of end points would be an awesome task within the
constraints of current technology and availability of funding (2).
Second, Vincenti et al comment insightfully on the
difficulty of delivering MMP inhibitors into target tissue,
e.g., bone or cartilage. With respect to the tetracyclinebased inhibitor known as CMT-1 (4-dedimethylaminotetracycline), oral administration of this agent (20 mg/kg) to rats
with adjuvant arthritis led to (extractable) levels of CMT-1
that ranged from 10 pg/gm (bone) to 20 pdgm (periarticular
soft tissue) (3). Additional studies on CMT-1 by Leung et al,
to be published in detail elsewhert (4), have yielded levels as
high as 70-114 pg/gm, which are far in excess of the
half-maximal inhibition concentration for rat paw MMP- 1 or
MMP-2. These effects, however, require concomitant administration of an antiinflammatory drug (e.g., flurbiprofen
or tenidap).
Finally, the review by Vincenti et al touches only
briefly on what is really the major hurdle in perfecting MMP
therapy for destructive arthritides, i.e., defining suitable
outcome measures for a study. Although tetracyclines, as an
example, have low-grade antiinflammatory effects, evaluation of their usefulness as MMP inhibitors in a disorder such
as rheumatoid arthritis using measures such as erythrocyte
sedimentation rates, joint counts, and walk times would
seem to have little face validity. A long list of potential
markers was discussed at the Tampa meeting (3,
but the
applicability of each suggested parameter remains to be
validated. The candidates include serum or urinary levels of
a variety of degradation products derived from connective
tissue macromolecules subject to MMP action, residual
connective tissue content, markers of regeneration, and
conventional assessments directed at MMP actions (radiologic, tissue integrity). For example, Chang et a1 have shown
convincingly that tetracyclines can totally inhibit bone loss
by a non-antiinflammatory action in an animal model (6).
Based on both animal and preliminary human data (7-9), I
would suggest that urinary pyridinium cross-link excretion is
currently the most attractive parameter of collagenase action
to be considered as a surrogate marker for demonstrating
effective in vivo MMP enzyme suppression.
Since there is no known agent that can be counted on
to arrest the progressive joint destruction in either rheumatoid arthritis or osteoarthritis, the intimidating obstacles that
stand between us and the goal of perfecting useful anti-MMP
therapy should not deter further efforts toward this end.
Robert A. Greenwald, MD, FACR
Long Island Jewish Medical Center
and Albert Einstein College of Medicine
New Hyde Park, N Y
1. Vincenti MP, Clark IM, Brinckerhoff CE: Using inhibitors of
metalloproteinases to treat arthritis: easier said then done?
Arthritis Rheum 31:1115-1126, 1994
Greenwald RA: Guidelines for clinical trial design for evaluation
of matrix metalloproteinase inhibitors: proceedings of a clinical
round table discussion, Inhibition of Matrix Metalloproteinases:
Therapeutic Potential, Tampa, FL, January 1994. Ann N Y Acad
Sci 132:213-279, 1994
Ramamurthy NS, Leung M, Moak SA, Greenwald R, Golub L:
CMTNSAID combination increases bone CMT uptake and
inhibits bone resorption. Ann N Y Acad Sci 696:420421, 1993
Leung M, Greenwald RA, Ramamurthy NS, Moak SA, Koszulinski R, Dieudonne D, Golub LM: NSAIDs enhance the uptake
of a matrix metalloproteinase inhibitor, 4-dedimethylaminotetracycline, by the inflamed joints of adjuvant arthritic rats. (in press)
Greenwald RA: Treatment of destructive arthritic disorders with
MMP inhibitors: potential role of tetracyclines, Inhibition of
Matrix Metalloproteinases: Therapeutic Potential, Tampa, FL,
January 1994. Ann N Y Acad Sci 132:181-198, 1994
Chang KM, Ramamurthy NS, McNamara TF, Evans RT,
Klausen B, Murray PA, Golub LM: Tetracyclines inhibit Porphyromonas gingivalis induced alveolar bone loss in rats by a
non-antimicrobial mechanism. J Periodont Res 29:242-249, 1994
Greenwald RA, Moak SA, Golub LM: Low dose doxycycline
(LDD) inhibits pyridinoline (PYD) excretion in selected patients
with rheumatoid arthritis, Inhibition of Matrix Metalloproteinases: Therapeutic Potential, Tampa, FL, January 1994. Ann N Y
Acad Sci 732:419-421, 1994
Greenwald RA, Moak SA, Chowdhury MH, Golub LM: Metalloproteinase inhibitors suppress pathologically excessive collagen
crosslink excretion in adjuvant arthritis (abstract). Arthritis
Rheum 36 (suppl 9):S45, 1993
Ganu V, Doughty S, Spirit0 S, Goldberg R: Elevation of urinary
pyridinioline in adjuvant arthritic rats and its inhibition by
doxycycline, Inhibition of Matrix Metalloproteinases: Therapeutic Potential, Tampa, FL, January 1994. Ann N Y Acad Sci
732:416-418, 1994
To the Editor:
We are pleased that our review article has prompted
such a positive response from other investigators in the field,
and we appreciate the opportunity to reply to the comments
of Dr. Greenwald.
We agree that the task of developing clinically efficacious inhibitors of MMPs is a formidable one. We also
agree that an inhibitor that is shown to be effective in vitro
may have limited effectiveness in patients due to problems
with delivery to appropriate tissues and/or degradation.
As pointed out by Dr. Greenwald, characterization
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