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The regulatory role of doxycyclinetetracycline in collagenolytic activity and tissue destruction in joint diseasescomment on the article by Yu et al.

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1335
LETTERS
relationships. We may find that even smaller continuous
doses have potent antiinflammatory effects.
This work is important since modern drug delivery
devices could bring some of the benefits of corticoids to our
patients at doses that may not be associated with unacceptable side effects. It may be, as James Russell Howell said,
that “new occasions teach new duties.”
G. S. Panayi, ScD, MD, FRCP
United Medical and Dental Schools
Guy’s Hospital
London, UK
1. Corkill MM, Kirkham BW, Chikanza IC, Gibson T, Panayi GS:
Intramuscular depot methylprenisolone induction of chrysotherapy in rheumatoid arthritis: a 24-week randomized controlled
trial. Br J Rheumatol 29:274-279, 1990
2. Choy EHS, Kingsley GH, Corkill MM, Panayi GS: Intramuscular and oral methylprednisolone during induction of chrysotherapy in rheumatoid arthritis (abstract). Br J Rheumatol 31 (suppl
2):35, 1992
The regulatory role of doxycycline/tetracycline in
collagenolytic activity and tissue destruction in joint
diseases: comment on the article by Yu et a1
To the Editor:
In a recent placebo-controlled study, Yu et a1 (1)
found that prophylactic administration of oral doxycycline
for 2 months markedly reduced the severity of osteoarthritis
in dogs. Tetracyclines and their non-antimicrobial derivatives are capable of inhibiting the activities of members of the
matrix metalloproteinase (MMP) family, especially preferring
human neutrophil collagenase (MMP-8) (2). In addition to this
direct inhibition, Yu et al suggested that doxycycline may
interfere with the conversion of latent procollagenases to
a catalytically active form of the enzyme. The mechanisms
of the prevention of procollagenase activation were not
addressed.
In addition to their activation by limited proteolysis,
procollagenases are known to be activated by reactive
oxygen species generated by inflammatory cells such as
polymorphonuclear leukocytes (3-5). We have recently
found that therapeutically attainable levels of lymecycline
(tetracycline-L-methylenelysine, which breaks down in vivo
to lysine and tetracycline, which serves as an active metabolite of the drug) do not directly inhibit neutrophil collagenase, but lymecycline at these levels can prevent the oxidative activation of latent human neutrophil collagenase in
vitro (6,7). Further support of this is provided by the finding
of Ramamurthy et a1 (8), that doxycycline in therapeutic
levels can prevent the oxidative activation of osteoblast
procollagenase. In our recent double-blind, placebocontrolled study of 3-month lymecycline treatment in reactive arthritis, it was found the the number of patients with
tissue destruction (as judged by radiographic changes) was
statistically significantly lower in the lymecycline-treated
group than in the placebo group (9), which may be due, at
least in part, to the anticollagenolytic potential of lymecycline shown in vitro (6,7).
Yu and colleagues also emphasized the importance
of the regulatory role of tissue inhibitor of metalloproteinases (TIMP), which represents a novel avenue for future
studies; however, we would further address the possible
important regulatory role of a,-proteinase inhibitor (al-PI).
Since both al-PI, which is another proteinase inhibitor,
namely, a serum protein and endogenous inhibitor of serine
proteinases (such as neutrophil elastase) and a substrate for
interstitial collagenases (3,10), and TIMP-1 can be oxidatively inactivated by reactive oxygen species (3,l l), it might
be possible that therapeutic levels of lymecycline/
doxycyclin+especially during long-term treatment-can
prevent general proteolytic events (in addition to specific
collagenolysis) by maintaining the action of the proteinase
inhibitor shield (6,7,10).
We further suggest that treatment with a combination
of long-term tetracycline/doxycycline medication and nonsteroidal antiinflammatory drugs (NSAIDs) may result in
more efficient prevention of tissue destruction, because
some NSAIDs, such as tenidap, are capable of preventing
the oxidative activation and release of procollagenase (12)
and because NSAIDs evidently reduce edema, thereby
facilitating entry of the tetracycline/doxycycline to the sites
of inflammation in vivo (13,141.
Supported by grants from the Academy of Finland and
NIDR grant R37-DE-03987.
A. Lauhio, MD
T. Sorsa, DDS, PhD
University of Helsinki
0 . Lindy, MD
University Central Hospital
K. Suomalainen, DDS
Aurora Hospital
Helsinki, Finland
H. Saari, MD, PhD
L. M. Golub, DMD, MSc
Y. T. Konttinen, MD, PhD
State University of New York at Stony Brook
Stony Brook, N Y
1. Yu LP Jr, Smith GN, Jr, Brandt KD, Myers SL, O’Connor BL,
Brandt DA: Reduction of the severity of canine osteoarthritis by
prophylactic treatment with oral doxycycline. Arthritis Rheum
35: 1150-1 159, 1992
2. Suomalainen K, Sorsa T, Golub LM, Ramamurthy NS, Lee
HM, Uitto V-J, Saari H, Konttinen YT: Specificity of the
anti-collagenase action of tetracyclines: relevance to their antiinflammatory potential. Antimicrob Agents Chemother 36:227229, 1992
3. Weiss SJ: Tissue destruction by neutrophils. N Engl J Med
320:365-376, 1989
4. Sorsa T, Saari H, Konttinen YT, Uitto V-J, Lindy S: Human
neutrophil collagenase and oxygen derived free radicals. N Engl
J Med 321:327-328, 1989
5. Konttinen YT, Lindy 0, Suomalainen K, Lauhio A, Saari H,
Vauhkonen M, Santavirta S, Sorsa T Substrate specificity and
activation mechanisms of collagenase from human rheumatoid
synovium. Matrix 11:395-403, 1991
6. Lauhio A, Sorsa T, Lindy 0, Suomalainen K, Saari H, Golub
LM, Konttinen YT: The anticollagenolytic potential of lymecycline in the long-term treatment of reactive arthritis. Arthritis
Rheum 35:195-198, 1992
1336
LETTERS
7. Lauhio A, Nordstrom D, Sorsa T, Rose S, Lindy 0, Golub LM,
Konttinen YT: Long-term treatment of reactive arthritis with
tetracycline, Prog Rheumatol (in press)
8. Ramamurthy NS, Greenwald RA, Vernillo A, Lee H-M, Golub
LM, Rifkin B: Oxygen radicals activate and tetracyclines inhibit
rat osteoblast collagenase (abstract). J Dent Res 71:757, 1992
9. Lauhio A, Leirisalo-Rep0 M, Lahdevirta J, Saikku P, Rep0 H:
Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 345-14, 1991
10. Sorsa T, Lindy 0, Konttinen YT, Suomalainen K, Ingman T,
Saari H, Halinen S, Lee H-M, Golub LM, Hall J, Simon S:
Doxycycline protects serum alpha-1-antitrypsin from human
neutrophil collagenase. Antimicrob Agents Chemother 37592594, 1993
1 1 . Stricklin G, Hoidart J: Oxidant-mediated inactivation of TIMP.
Matrix 12 (suppl 1):325-326, 1992
12. Blackburn WD Jr, Loose LD, Heck LW, Chatham WW:
Tenidap, in contrast to several available nonsteroidal antiinflammatory drugs, potently inhibits the release of activated
neutrophil collagenase. Arthritis Rheum 34:211-216, 1991
13. Ramamurthy N, Leung M, Moak S, Greenwald R, Golub L:
CMT/NSAID combination increases bone CMT uptake and
inhibits bone resorption (abstract). J Dent Res 72:333, 1993
14. Greenwald RA, Ramamurthy NS, Moak SA, Golub LM: Metalloproteinase activity and radiologic severity of adjuvant arthritis: synergistic beneficial effects of tenidap and 4-dedimethylamine tetracycline (abstract). Arthritis Rheum 35 (suppl 9):
S131. 1992
considerable interest. However, the importance of reactive
oxygen species in tissue destruction in OA is unclear. The
possibility that tetracyclines inhibit cartilage breakdown by
protecting TIMP and al-PI from inactivation by oxidative
mechanisms may also be relevant to OA since both TIMP (3)
and a1-PI (4) are synthesized by chondrocytes.
Use of an NSAID in combination with long-term
tetracycline treatment in OA, as suggested by Lauhio et al,
should be viewed with some caution since in vitro studies
suggest that some NSAIDs inhibit proteoglycan synthesis
and, hence, repair activity of the OA chrondrocyte (5). Data
from experimental models of OA indicate that, at least with
salicylate, this occurs also in vivo, accelerating cartilage
breakdown in the OA joint (6). While there are no data at
present to indicate that regular NSAID treatment has a
similar effect in humans with OA, studies aimed at examining this possibility are in progress.
Reply
1 . Poole AR: Enzymatic degradation: cartilage destruction, Cartilage Changes in Osteoarthritis. Edited by KD Brandt. Indianapolis, Indiana University School of Medicine, 1990
2. Lauhio A, Sorsa T, Lindy 0, Suomalainen K, Saari H, Golub
LM, Konttinen YT: The anticollagenolytic potential of lymecycline in the long-term treatment of reactive arthritis. Arthritis
Rheum 35:195-198, 1992
3. Morales TI, Kuettner KE, Howell DS, Woessner J F Jr: Characterization of the metalloproteinase inhibitor produced by bovine
articular chondrocyte cultures. Biochim Biophys Acta 760:221229, 1983
4. Wood DJ, Awbrey BJ, Mankin HJ, Treadwell BV: Synthesis of
alpha-1-antitrypsin by human articular chondrocytes. Trans Orthop Res SOC15:184, 1990
5 . Palmoski MJ, Brandt KD: Effects of some nonsteroidal antiinflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum 23:1010-1020,
1980
6. Palmoski MJ, Brandt KD: In vivo effect of aspirin on canine
osteoarthritic cartilage. Arthritis Rheum 26:9941001, 1983
To the Editor:
We thank Dr. Lauhio and colleagues for their comments about our recent study showing that prophylactic
administration of doxycycline reduced the severity of joint
damage in a canine model of osteoarthritis (OA). As we
indicated in our report and as Lauhio et a1 emphasize in their
letter, the mechanism(s) underlying the observed in vivo
effect is not clear, although it was shown to be associated
with suppression of collagenase and gelatinase activities in
extracts of the OA cartilage. The activation of matrix metalloproteases in cartilage involves a cascade of proteolytic
events (l), and the precise mechanism by which doxycycline
inhibits metalloprotease activity in OA cartilage is unknown.
The observation by Lauhio et a1 that tetracycline,
derived from the in vivo breakdown of lymecycline, did not
directly inhibit neutrophil collagenase, but prevented in vitro
oxidation of human neutrophil procollagenase (Z), is of
Kenneth D. Brandt, MD
L. P. Yu, Jr., MD
G. N. Smith, Jr., PhD
S. L. Myers, MD
B. L. O’Connor, PhD
D. A. Brandt, BA
Indiana University School of Medicine
Indianapolis, IN
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