Condylar Resorption, Matrix Metalloproteinases, and Tetracyclines

Michael J. Gunson, DDS, MD ■ G. William Arnett, DDS, FACD

Mi c h a e l J. Gu n s o n , DDS, MD Summary [email protected] Mandibular condylar resorption occurs as a result of inflammation and hor- ■ Graduated from UCLA School of mone imbalance. The cause of the bone loss at the cellular level is secondary Dentistry, 1997 to the production of matrix metalloproteinases (MMPs). MMPs have been ■ Graduated from UCLA School of Medicine 2000 shown to be present in diseased temporomandibular joints (TMJs). There is ■ Specialty Certificate in Oral and evidence that tetracyclines help control bone erosions in arthritic joints by Maxillofacial Surgery UCLA, 2003 inactivating MMPs. This article reviews the pertinent literature in support of using tetracyclines to prevent mandibular condylar resorption. G. Wi ll i a m Ar n e tt , DDS, FACD ■ Graduated from USC School of Dentistry, 1972 ■ Specialty Certificate in Oral and Maxillofacial Surgery UCLA, 1975

Introduction has been well studied. A number of cytokines and proteases Orthodontists and maxillofacial surgeons are well acquaint- are found in joints that show osseous erosions that are not ed with the effects of condylar resorption (Figure 1). present in healthy joints, namely TNF-α, IL-1β, IL-6, and RANKL and matrix metalloproteinases.

Matrix Metalloproteinases 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, cirrho- sis, 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 incorporat- Figure 1 Tomograms reconstructed from cone-beam CT scan. ed. The zymogen is then cleaved into the extracellular matrix They show severe condylar resorption in a 19-year-old female as the active enzyme, where it makes cuts into the protein over a 2-year period. Note the progressive osseous destruction. chains (collagen types I through IV, gelatin, etc). These cuts cause the proteins to denature, which results in the destruc- The clinical outcomes of condylar resorption have been de- tion of the matrix. The action of the MMP requires the min- scribed at length in the literature.1-6 The causes, however, eral zinc—which is an important part of the MMP’s protein have been elusive, hence the common name idiopathic con- structure; hence the name metalloproteinase (Figure 2). dylar resorption. Over the last several years, the pathophysi- ology of articular bone erosion secondary to inflammation

RWISO Journal | September 2010 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 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 3 A list of the 28 known MMPs. They are generally named after the extracellular protein that they degrade. Figure 4-b MMP transcription is inhibited by hormones such The extracellular activity of MMPs is regulated in two as vitamin D and estradiol, as well as the bone-protective ways, by transcription and by extracellular inhibition. The cytokine osteoprotegerin. 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, IL- 1β, 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 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 unreg- ulated degradation of tissue by MMPs. 35, 36

Tetracyclines Because MMPs are found to be elevated in patients with TMJ arthritis and are so destructive to articular tissues, find- ing a way to reduce their activity or their production would be helpful in treating patients with arthritis and condylar Figure 4-c The extracellular activity of MMPs is controlled by the resorption. presence of inhibitory proteins called tissue inhibitors of metalloproteinases, or TIMPs. TIMPs bind directly to the From 1972-1982, at the School of Dental Medicine in MMPs, causing conformational changes that prevent the Stony Brook New York, Ramurmathy and Golub discov- destruction of matrix proteins. ered that tetracyclines have anti-collagenolytic properties. In 1998, Golub and colleagues showed that tetracyclines MMPs and Arthritis inhibit bone resorption in two ways—by controlling the ex- The hallmark sign of arthritis is articular bone loss. In the pression and activity of MMPs and by regulating osteoclasts past, clinicians have differentiated between inflammatory ar- and their activity.37 thritis and osteoarthritis (OA). Recently, however, the cellular processes that result in bone and cartilage loss in both forms Controlling MMPs With Tetracyclines of arthritis have been shown to be quite similar.11 While in- Tetracyclines inhibit MMPs by chelating zinc and by regu- flammatory arthritis is promoted by a systemic problem, the lating MMP gene expression. As noted above, MMPs need result is an inflammatory cytokine cascade, which ultimately zinc to actively cleave collagen proteins. Tetracyclines bind results in osteoclastic activity and bone loss at the articular divalent ions, such as zinc. By reducing the amount of free surface. OA is not a systemic problem but a local one, second- zinc in tissues, tetracyclines reduce the number of MMPs ary to oxidation reactions, free radical production, or sheer available.38 In addition, tetracyclines bind to the MMP itself, stress—all three of which result from overuse.12, 13 Despite which causes a conformational change in the enzyme, inacti- the localized nature of OA, the cascade of cellular events that vating it (Figure 5).39 Tetracyclines have also been shown to cause articular surface loss is the same as the systemically in- decrease the transcription of MMPs by blocking both produced cascade. An increase in TNF- and IL-1 increases the α β tein kinase C and calmodulin pathways.40, 41 number of osteoclasts and their activity. TNF-α, IL-1β, IL- 6, 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 as- sociation 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 Figure 5 Tetracycline binds directly to the zinc of the MMP. There is substantial evidence indicating that MMPs play an This deactivates the enzyme and protects the matrix important role in bone and cartilage degradation associated from degradation. Tetracycline also controls osteoclastic with degenerative temporomandibular joint (TMJ) arthriti- activity and MMP transcription.

RWISO Journal | September 2010 39 Regulating Osteoclasts With Tetracyclines racyclines may be considered for the treatment of rapidly Osteoclasts are responsible for the breakdown of bone and progressive condylar resorption, and in patients with degen- cartilage. Their activity is tightly controlled by cytokines erative TMJ disease. They may also be used in patients at in- such as IL-6, TNF-α, nitric oxide, and IL-1β. Tetracyclines creased risk for resorption. This includes patients with brux- have been shown to prevent the liberation of these cytokines, ism, inflammatory arthritis, or a past history of resorption diminishing the activity of osteoclasts.42-46 Tetracyclines also who are undergoing occlusal treatment. Of all the available prevent the differentiation of osteoclast precursor cells into tetracyclines, Golub et al found that doxycycline was the osteoclasts.47 Finally, tetracyclines promote the programmed most effective at suppressing MMP activity.56 Appropriate cell death (apoptosis) of osteoclasts.48, 49 All these actions re- studies to determine effective dose schedules have not been sult in a decrease of bone and cartilage loss secondary to conducted to date. However, based on the limited clinical osteoclast activity when tetracyclines are present. data, it is reasonable to consider doxycycline at a dose of 50 mg twice daily. Tetracyclines and Arthritis In short, the literature shows that tetracyclines exert control Side Effects over MMP transcription and activity and regulate osteoclast The adverse effects of tetracyclines are well known. They activity as well. The clinical evidence supporting the use of include allergic reactions; gastrointestinal symptoms (ulcers, tetracyclines to protect articular bone and cartilage from ar- nausea, vomiting, diarrhea, Candida superinfection); photo- thritic inflammation is encouraging. sensitivity; vestibular toxicity with vertigo and tinnitus; de- In the animal model of arthritis, tetracyclines have been creased bone growth in children; and discoloration of teeth shown to inhibit MMPs and to prevent the progression of if administered during tooth development. Tetracyclines may osseous disease.50-52 Yu et al52 induced knee arthritis in dogs also reduce the effectiveness of oral contraceptives, potenti- by severing the anterior cruciate ligament. Half the dogs ate lithium toxicity, increase digoxin availability and toxic- were pretreated with doxycycline. Doxycycline prevented ity, and decrease prothrombin activity.57 the full-thickness cartilage ulcerations that were seen in the If tetracycline therapy is initiated, the patient should be untreated group. advised of the potential for reduced efficacy of oral contra- In human studies, tetracyclines have been successfully ception. In addition, the patient should be cautioned against used to diminish bone erosions in patients with inflammato- sun exposure, and should be monitored for other side effects. ry arthritis. One meta-analysis of 10 clinical trials that used If surgery is contemplated, the patient’s coagulation status tetracycline for rheumatoid arthritis (RA) showed significant should be evaluated. improvement in disease activity with no side effects.53 In a There is some question as to whether bacterial resis- single-blinded controlled study, doxycycline was shown to tance may develop with the chronic use of antibiotics. Stud- be as effective as methotrexate in treating inflammatory ar- ies show that long-term low-dose doxycycline (20 mg twice thritis.54 daily) does not lead to a significant increase in bacterial resis- Israel et al reported that doxycycline administered at a tance or to a change in fecal or vaginal flora.58, 59 dose of 50 mg twice daily for 3 months significantly suppressed MMP activity in three patients diagnosed with ad- Other Medications to Control MMPs vanced osteoarthritis of the TMJ. Two of the three patients Tetracyclines are not the only medications that can prevent reported marked improvement in symptoms, including im- MMP-induced bone erosions. There are promising studies proved mandibular range of motion. One patient did not that show the benefits of TNF-α inhibitors; osteoprotegerin experience symptomatic relief despite a marked reduction in analogues; HMG-CoA reductase inhibitors (eg, simvasta- MMP activity.55 While symptomatic relief would be impor- tin); and hormone replacement therapies, including vitamin tant, it must be noted that inhibition of MMPs has a direct D and estradiol.60-63 These medications, along with doxycy- effect on bony resorption, which is often unrelated to TMJ cline, show great promise in controlling articular bone loss symptoms. Clinicians need to keep this in mind when re- in the face of inflammation. viewing the literature. Conclusion Dosing When patients present with condylar resorption, clinicians At present, there are no definitive studies demonstrating the have long been resigned to two choices: watch and wait or efficacy of tetracycline therapy for degenerative -TMJ ar surgical resection with the resulting disability and deformity. thritides. However, based on the available information, tet- Doxycycline is just one pharmacological intervention that

40 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.

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44 Gunson, Arnett | Condylar Resorption, Matrix Metalloproteinases, and Tetracyclines