Condylar Resorption, Matrix Metalloproteinases

Condylar Resorption, Matrix Metalloproteinases,
and Tetracyclines
Michael J. Gunson, DDS, MD ■ G. William Arnett, DDS, FACD
M ichael J. G unson , DDS, MD
[email protected]
■ Graduated from UCLA School of
Dentistry, 1997
■ Graduated from UCLA School of
Medicine 2000
■ Specialty Certificate in Oral and
Maxillofacial Surgery UCLA, 2003
G. William A rnett , DDS, FACD
■ Graduated from USC School of
Dentistry, 1972
■ Specialty Certificate in Oral and
Maxillofacial Surgery UCLA, 1975
Summary
Mandibular condylar resorption occurs as a result of inflammation and hormone imbalance. The cause of the bone loss at the cellular level is secondary
to the production of matrix metalloproteinases (MMPs). MMPs have been
shown to be present in diseased temporomandibular joints (TMJs). There is
evidence that tetracyclines help control bone erosions in arthritic joints by
inactivating MMPs. This article reviews the pertinent literature in support of
using tetracyclines to prevent mandibular condylar resorption.
Introduction
Orthodontists and maxillofacial surgeons are well acquainted with the effects of condylar resorption (Figure 1).
has been well studied. A number of cytokines and proteases
are found in joints that show osseous erosions that are not
present in healthy joints, namely TNF-α, IL-1β, IL-6, and
RANKL and matrix metalloproteinases.
Matrix Metalloproteinases
Figure 1 Tomograms reconstructed from cone-beam CT scan.
They show severe condylar resorption in a 19-year-old female
over a 2-year period. Note the progressive osseous destruction.
The clinical outcomes of condylar resorption have been described at length in the literature.1-6 The causes, however,
have been elusive, hence the common name idiopathic condylar resorption. Over the last several years, the pathophysiology of articular bone erosion secondary to inflammation
MMPs are of interest because they are directly responsible
for the enzymatic destruction of extracellular matrix in normal conditions (angiogenesis, morphogenesis, tissue repair)
and in pathological conditions (arthritis, metastasis, cirrhosis, endometriosis). MMPs are endopeptidases that are made
in the nucleus as inactive enzymes, or zymogens. The zymogens travel to the cell membrane, where they are incorporated. The zymogen is then cleaved into the extracellular matrix
as the active enzyme, where it makes cuts into the protein
chains (collagen types I through IV, gelatin, etc). These cuts
cause the proteins to denature, which results in the destruction of the matrix. The action of the MMP requires the mineral zinc—which is an important part of the MMP’s protein
structure; hence the name metalloproteinase (Figure 2).
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37
porated. Activation of the MMP occurs when the active side
of the MMP is cleaved from the cell and liberated into the extracellular matrix. Extracellular inhibition comes from proteins called tissue inhibitors of metalloproteinases (TIMPs).
TIMPs bind to active matrix metalloproteinases and inhibit
their activity (Figure 4c). The ratio of MMP:TIMP activity
influences the amount of matrix degradation.7-10
Figure 2 The zymogen pro-MMP is transcribed in the nucleus
and then attached to the cell membrane. It is activated when
it is cleaved from the membrane. The zinc (Zn) portion binds
to protein and the enzyme cleaves the protein, destroying the
extracellular matrix.
In joints, MMPs are produced by monocytes, macrophages, polymorphonuclear neutrophils, synoviocytes, osteoblasts, and osteoclasts. MMPs are generally classified by
the kind of matrix they degrade; thus collagenase, gelatinase
and stromelysin (Figure 3).
Figure 3 A list of the 28 known MMPs. They are generally
named after the extracellular protein that they degrade.
The extracellular activity of MMPs is regulated in two
ways, by transcription and by extracellular inhibition. The
transcription of MMPs in the nucleus is controlled by multiple pathways. MMP transcription is activated by sheer stress
to the cell, by free radicals, and by the cytokines TNF-α, IL1β, Il-6 and RANKL (Figure 4a). Transcription is suppressed
by the cytokine osteoprotegerin and by the the hormones
vitamin D and estradiol (Figure 4b). After transcription, the
pro-MMP is then sent to the cell membrane, where it is incor-
38
Figure 4-a MMP transcription is activated in the cell nucleus by
cytokines (TNF-α, IL-1β, Il-6, and RANKL); by metabolic
by-products (free radicals); and by direct sheer stress
to the cell membrane.
Figure 4-b MMP transcription is inhibited by hormones such
as vitamin D and estradiol, as well as the bone-protective
cytokine osteoprotegerin.
Gunson, Arnett | Condylar Resorption, Matrix Metalloproteinases, and Tetracyclines
des. This evidence supports the presence of 6 of the known
28 matrix metalloproteinases (MMP-1, MMP-2, MMP-3,
MMP-8, MMP-9, and MMP-13) in fluid or tissue samples
obtained from diseased human TMJs.13, 16, 17, 19-34 Some cases
of degenerative joint disease also result from an imbalance
between the activities of MMPs and TIMPs, favoring unregulated degradation of tissue by MMPs. 35, 36
Tetracyclines
Figure 4-c The extracellular activity of MMPs is controlled by the
presence of inhibitory proteins called tissue inhibitors of
metalloproteinases, or TIMPs. TIMPs bind directly to the
MMPs, causing conformational changes that prevent the
destruction of matrix proteins.
MMPs and Arthritis
The hallmark sign of arthritis is articular bone loss. In the
past, clinicians have differentiated between inflammatory arthritis and osteoarthritis (OA). Recently, however, the cellular
processes that result in bone and cartilage loss in both forms
of arthritis have been shown to be quite similar.11 While inflammatory arthritis is promoted by a systemic problem, the
result is an inflammatory cytokine cascade, which ultimately
results in osteoclastic activity and bone loss at the articular
surface. OA is not a systemic problem but a local one, secondary to oxidation reactions, free radical production, or sheer
stress—all three of which result from overuse.12, 13 Despite
the localized nature of OA, the cascade of cellular events that
cause articular surface loss is the same as the systemically induced cascade. An increase in TNF-α and IL-1β increases the
number of osteoclasts and their activity. TNF-α, IL-1β, IL6, and RANKL all cause increased expression of the MMP
genes. The end result is destruction of cartilage, bone, and
connective tissue in both arthritis models.14-18
MMPs also respond to systemic hormones such as estrogen, vitamin D, and parathyroid hormones. We found an association between low estrogen levels and low vitamin D levels in patients with severe condylar resorption.3 All of these
hormones and cytokines are intimately involved in osteoclast
differentiation and activation. This makes sense: MMPs are
osteoclast produced and are responsible for bone and cartilage destruction.
MMPs and the TMJ
There is substantial evidence indicating that MMPs play an
important role in bone and cartilage degradation associated
with degenerative temporomandibular joint (TMJ) arthriti-
Because MMPs are found to be elevated in patients with
TMJ arthritis and are so destructive to articular tissues, finding a way to reduce their activity or their production would
be helpful in treating patients with arthritis and condylar
resorption.
From 1972-1982, at the School of Dental Medicine in
Stony Brook New York, Ramurmathy and Golub discovered that tetracyclines have anti-collagenolytic properties.
In 1998, Golub and colleagues showed that tetracyclines
inhibit bone resorption in two ways—by controlling the expression and activity of MMPs and by regulating osteoclasts
and their activity.37
Controlling MMPs With Tetracyclines
Tetracyclines inhibit MMPs by chelating zinc and by regulating MMP gene expression. As noted above, MMPs need
zinc to actively cleave collagen proteins. Tetracyclines bind
divalent ions, such as zinc. By reducing the amount of free
zinc in tissues, tetracyclines reduce the number of MMPs
available.38 In addition, tetracyclines bind to the MMP itself,
which causes a conformational change in the enzyme, inactivating it (Figure 5).39 Tetracyclines have also been shown to
decrease the transcription of MMPs by blocking both protein kinase C and calmodulin pathways.40, 41
Figure 5 Tetracycline binds directly to the zinc of the MMP.
This deactivates the enzyme and protects the matrix
from degradation. Tetracycline also controls osteoclastic
activity and MMP transcription.
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Regulating Osteoclasts With Tetracyclines
Osteoclasts are responsible for the breakdown of bone and
cartilage. Their activity is tightly controlled by cytokines
such as IL-6, TNF-α, nitric oxide, and IL-1β. Tetracyclines
have been shown to prevent the liberation of these cytokines,
diminishing the activity of osteoclasts.42-46 Tetracyclines also
prevent the differentiation of osteoclast precursor cells into
osteoclasts.47 Finally, tetracyclines promote the programmed
cell death (apoptosis) of osteoclasts.48, 49 All these actions result in a decrease of bone and cartilage loss secondary to
osteoclast activity when tetracyclines are present.
Tetracyclines and Arthritis
In short, the literature shows that tetracyclines exert control
over MMP transcription and activity and regulate osteoclast
activity as well. The clinical evidence supporting the use of
tetracyclines to protect articular bone and cartilage from arthritic inflammation is encouraging.
In the animal model of arthritis, tetracyclines have been
shown to inhibit MMPs and to prevent the progression of
osseous disease.50-52 Yu et al52 induced knee arthritis in dogs
by severing the anterior cruciate ligament. Half the dogs
were pretreated with doxycycline. Doxycycline prevented
the full-thickness cartilage ulcerations that were seen in the
untreated group.
In human studies, tetracyclines have been successfully
used to diminish bone erosions in patients with inflammatory arthritis. One meta-analysis of 10 clinical trials that used
tetracycline for rheumatoid arthritis (RA) showed significant
improvement in disease activity with no side effects.53 In a
single-blinded controlled study, doxycycline was shown to
be as effective as methotrexate in treating inflammatory arthritis.54
Israel et al reported that doxycycline administered at a
dose of 50 mg twice daily for 3 months significantly suppressed MMP activity in three patients diagnosed with advanced osteoarthritis of the TMJ. Two of the three patients
reported marked improvement in symptoms, including improved mandibular range of motion. One patient did not
experience symptomatic relief despite a marked reduction in
MMP activity.55 While symptomatic relief would be important, it must be noted that inhibition of MMPs has a direct
effect on bony resorption, which is often unrelated to TMJ
symptoms. Clinicians need to keep this in mind when reviewing the literature.
racyclines may be considered for the treatment of rapidly
progressive condylar resorption, and in patients with degenerative TMJ disease. They may also be used in patients at increased risk for resorption. This includes patients with bruxism, inflammatory arthritis, or a past history of resorption
who are undergoing occlusal treatment. Of all the available
tetracyclines, Golub et al found that doxycycline was the
most effective at suppressing MMP activity.56 Appropriate
studies to determine effective dose schedules have not been
conducted to date. However, based on the limited clinical
data, it is reasonable to consider doxycycline at a dose of 50
mg twice daily.
Side Effects
The adverse effects of tetracyclines are well known. They
include allergic reactions; gastrointestinal symptoms (ulcers,
nausea, vomiting, diarrhea, Candida superinfection); photosensitivity; vestibular toxicity with vertigo and tinnitus; decreased bone growth in children; and discoloration of teeth
if administered during tooth development. Tetracyclines may
also reduce the effectiveness of oral contraceptives, potentiate lithium toxicity, increase digoxin availability and toxicity, and decrease prothrombin activity.57
If tetracycline therapy is initiated, the patient should be
advised of the potential for reduced efficacy of oral contraception. In addition, the patient should be cautioned against
sun exposure, and should be monitored for other side effects.
If surgery is contemplated, the patient’s coagulation status
should be evaluated.
There is some question as to whether bacterial resistance may develop with the chronic use of antibiotics. Studies show that long-term low-dose doxycycline (20 mg twice
daily) does not lead to a significant increase in bacterial resistance or to a change in fecal or vaginal flora.58, 59
Other Medications to Control MMPs
Tetracyclines are not the only medications that can prevent
MMP-induced bone erosions. There are promising studies
that show the benefits of TNF-α inhibitors; osteoprotegerin
analogues; HMG-CoA reductase inhibitors (eg, simvastatin); and hormone replacement therapies, including vitamin
D and estradiol.60-63 These medications, along with doxycycline, show great promise in controlling articular bone loss
in the face of inflammation.
Conclusion
Dosing
At present, there are no definitive studies demonstrating the
efficacy of tetracycline therapy for degenerative TMJ arthritides. However, based on the available information, tet-
40
When patients present with condylar resorption, clinicians
have long been resigned to two choices: watch and wait or
surgical resection with the resulting disability and deformity.
Doxycycline is just one pharmacological intervention that
Gunson, Arnett | Condylar Resorption, Matrix Metalloproteinases, and Tetracyclines
shows promise in curbing the bone loss associated with arthritis and condylar resorption (Figures 6-a, b, c, d, e). ■
Figure 6-a, b, c, d, e This is a 31-year-old patient with condylar
resorption secondary to rheumatoid arthritis. She was treated
with orthognathic surgery to correct her malocclusion. The
effects of MMPs were controlled pre- and postoperatively by
prescribing the following medications: doxycycline, simvastatin,
Enbrel, Feldene, vitamin D, and omega-3 fatty acids. She is 10
months postsurgery with minimal osseous change to her condyles
and a stable class I occlusion with good overbite and overjet.
RWISO Journal | September 2010
41
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