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ARTHRITIS & RHEUMATISM
Vol. 64, No. 1, January 2012, pp 37–39
DOI 10.1002/art.33330
© 2012, American College of Rheumatology
EDITORIAL
Changing the Outcome of Osteoarthritis: Still a Challenge for
Cyclooxygenase 2 Inhibitors
Rik J. U. Lories
zymes acting downstream of the COX enzymes in
prostaglandin synthesis, were expressed in normal cartilage but appeared to be down-regulated in OA cartilage.
In contrast, inducible COX-2 and mPEGS-1 were upregulated in OA cartilage but absent in normal cartilage.
Treatment with celecoxib, a specific COX-2 inhibitor
currently used in clinical practice for OA symptom
relief, did not affect histopathologic severity scores for
cartilage damage and osteophyte formation in Fukai and
colleagues’ study. Moreover, the outcome in this specific
mouse model was not different between wild-type mice
and mice in which the Ptgs1 and Ptgs2 genes, coding for
COX-1 and COX-2, respectively, were deleted.
COX inhibition, and in particular inhibition of
COX-2, could exert structural effects on disease progression by interfering with different processes in distinct
joint tissues. This includes a direct impact on cartilage or
subchondral bone homeostasis, and additional effects on
osteophyte formation and on synovial inflammation,
dampening the production of cytokines and cartilage
matrix–degrading enzymes. In the last few years, there
has indeed been accumulating evidence that COX-2 may
play a role in the progression of OA. Studies performed
in Utrecht, The Netherlands have raised particular
interest. In vitro work using OA cartilage explants
suggested that not only celecoxib but also aceclofenac,
which is considered to preferentially inhibit COX-2 over
COX-1, had beneficial effects on proteoglycan synthesis
and improved explant proteoglycan content, whereas the
nonspecific COX inhibitors indomethacin and naproxen
did not (3). However, these results could not be confirmed in the in vivo setting: celecoxib treatment of dogs
in the canine groove model of OA did not demonstrate
any benefit despite the observations that celecoxib was
found in detectable amounts in the synovial fluid and
that canine explants benefited from in vitro celecoxib
treatment (4).
An ex vivo analysis of a 15-week in vivo intervention with celecoxib in patients awaiting knee replacement surgery did suggest that COX-2 inhibition had
Making a choice between analgesics such as
acetaminophen and nonsteroidal antiinflammatory
drugs (NSAIDs) when treating patients with pain caused
by osteoarthritis (OA) can be difficult. Current guidelines support the use of analgesics as a first choice, but
NSAIDs may be slightly superior for improving pain (1).
However, NSAIDs are associated with increased toxicity
and side effects. Patients often turn to their physicians
only after self-treatment with analgesics has failed.
NSAIDs target the cyclooxygenase (COX) enzymes, key
enzymes in the synthesis of prostaglandins. Inhibition of
COX-1 often results in gastrointestinal adverse effects
whereas the cardiovascular safety of COX-2 inhibitors
has been heavily debated, in particular for elderly patients who have additional cardiovascular risk factors.
Weighing the different options could be either simpler
or even more complex if NSAIDs were to be shown to
have an effect on the structural progression of disease,
and thereby on long-term outcome.
The consequences of inhibiting COX enzymes on
both cartilage and bone biology have been studied
extensively. However, findings indicating potential effects on structural progression of OA have been contradictory, and current concepts remain largely based on in
vitro experiments. This is further complicated by the
hypothesis that more efficient pain control could result
in increased joint use and strain in vivo, thereby accelerating disease progression.
In this issue of Arthritis & Rheumatism, Fukai et al
report on the lack of chondroprotection by specific
COX-2 inhibition in a surgically induced model of OA in
mice (2). COX-1, as well as microsomal prostaglandin E
synthase 2 (mPGES-2) and cytosolic PGES, two enRik J. U. Lories, MD, PhD: Katholieke Universiteit Leuven,
Leuven, Belgium.
Address correspondence to Rik J. U. Lories, MD, PhD,
Laboratory for Skeletal Development and Joint Disorders, Division of
Rheumatology, UZ Leuven, Herestraat 49, B3000 Leuven, Belgium.
E-mail: [email protected]
Submitted for publication August 22, 2011; accepted August
30, 2011.
37
38
beneficial and specific effects in these patients with
end-stage disease (5). Obviously the clinical impact of
these findings remains to be further studied in trials with
patients in whom inhibition of structural disease progression can still affect the outcome. Other in vivo
studies used nuclear magnetic resonance imaging (MRI)
of cartilage thickness as an outcome measure. In a
cohort of 395 elderly subjects, treatment with selective
COX-2 inhibitors appeared to have beneficial effects
whereas treatment with nonselective NSAIDs had deleterious effects; however, the number of patients receiving each of these treatments was small (40 and 21,
respectively) (6). In contrast, a recent open-label pilot
study did not demonstrate a beneficial effect on cartilage, as determined by MRI, after 12 months of celecoxib treatment, compared to historical controls (7).
These preliminary data do suggest that there is room for
well-defined interventional clinical trials assessing the
issue.
From the biologic perspective, COX-2 is a highly
inducible and regulated enzyme, and is typically found in
response to inflammatory signals and cell stress. COX-1,
in contrast, is the homeostatic isoform of the enzyme
and often disappears when a tissue is challenged. In
cartilage, the PGE receptor EP4 is a downstream mediator of the deleterious effects of COX-2 activation and
PGE2 synthesis, and could represent a more specific
therapeutic target to inhibit disease progression (8).
Another notable finding of the study by Fukai et
al (2) was the absence of an effect on osteophyte
formation. Again, two different explanations can be
proposed. Effective treatment of pain with the use of
celecoxib in this study may have increased mobility in
the treated mice compared to the control group. Exposure to instability may trigger repair-like efforts such as
osteophyte formation, in order to stabilize the joint.
Since COX-2 inhibition delays fracture healing and is
used to prevent heterotopic ossification after prosthesis
surgery (9), the lack of effect could also suggest that the
driving mechanisms or progenitor cell populations involved are different in the surgically induced OA model
than in the above-mentioned situations. This could be of
specific clinical interest as systematic treatment with
celecoxib has been demonstrated to delay progression of
spinal ankylosis in ankylosing spondylitis, a chronic
inflammatory disease of the spine and sacroiliac joints
(10). Again, inflammation versus instability as the factor
inducing new bone formation, as well as differences in
target cells (progenitor cells in the entheseal attachment
zones versus in the periosteum), can explain some of the
LORIES
discrepant findings, but direct comparisons in specific
models are lacking to date.
Taking all of this into account, the report by
Fukai and colleagues nicely illustrates both some of the
strengths and some of the limitations of using mouse
models of human disease in a translational setting for
clinicians and basic scientists. Over the last decade new
animal models of OA have been developed and optimized. Microsurgical procedures leading to mild or
severe instability in the knee joints of mice or rats
appear to yield models that resemble the human disease
processes much more closely than the chemical or
enzymatic models that formerly took center stage. The
availability of genetic models with deletion or overexpression of specific genes, at either the organism or the
tissue level, has provided the research community an
increasing number of tools with which to tackle complex
translational research questions. Efforts have also been
made to standardize microscopic scoring of disease
processes. Nevertheless, when studying genetically modified animals, specific attention should be given to the
impact of abnormalities in tissues that may not be the
direct focus of the experiment. For instance, many mice
in which genes relevant for cartilage biology have been
modified may also have a bone phenotype that could
affect the biomechanical balance between articular cartilage and subchondral bone.
The absence of an effect of celecoxib treatment in
the study by Fukai et al and the relevance of this finding
to the human disorder could be challenged, as pharmacokinetics and dosages are rarely optimized in rodent
models. For example, suboptimal dosing could result in
rebound effects, shifting the observations to the opposite
direction. The authors tried to partially overcome this
issue by also using Ptgs1- and Ptgs2-knockout mice; in
those experiments, OA development in the knockout
mice did not differ from that in wild-type mice. Of
interest, mice with gene deletions for proinflammatory
cytokines such as interleukin-1 and tumor necrosis factor
␣ also did not exhibit increased cartilage damage in this
model.
At first glance the main advantage of rodent
models is that they enable straightforward and complete
pathologic analysis with direct evaluation of structural
damage. However, each of the currently used models has
its limitations, and OA progression in all of them is
clearly accelerated compared to the slowly developing
human disease. Scoring systems for mice may lack detail
and discriminatory value, and negative results as described by Fukai et al should always be viewed with
caution. In addition, as mentioned above, reduction of
EDITORIAL
39
joint pain may lead to increased mobility and thus more
strain in the model, an issue that was only partially
addressed by Fukai and colleagues.
In summary, the findings reported by Fukai et al
should stimulate further discussion about the use of
NSAIDs, and in particular, specific COX-2 inhibitors, in
OA. Emerging well-defined clinical trials and the development of imaging end points are encouraging. Paying
close attention to the experience obtained in small
animal models is essential and should motivate clinical
investigators to carefully define their target populations
and protocols. Most importantly, when drawing conclusions from both human and animal studies, investigators
should not always aim for broad generalization and
should avoid overstating the translatability of the data.
The wave of enthusiasm for translational research based on either patient samples or specific animal
models to solve clinically relevant questions entails the
considerable risk of drifting away from the hard data
toward emphasizing potential but unproven effects in
patients. A particular effect on structural disease progression may be achieved only in specific patient subsets,
putting the emphasis for the future of OA treatment on
personalized medicine that takes into account potential
adverse effects, the extent and stage of the disease
process, and likely also the genetic profile. Indeed,
PTGS2 has been identified as a susceptibility gene for
knee OA in a genome-wide association study (11). These
polymorphisms may have an effect on the tissue in the
joint but also on the severity of pain and inflammation or
even the efficacy of drugs, highlighting once again the
complex impact of COX enzymes on OA.
AUTHOR CONTRIBUTIONS
Dr. Lories drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
REFERENCES
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