2010 RWISO Journal - Roth Williams International Society of ...

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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, mac- rophages, 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, 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 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 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.
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, 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 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- 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- 35, 36 ulated degradation of tissue by MMPs. Tetracyclines 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 pro- 40, 41 tein kinase C and calmodulin pathways. 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. RWISO Journal | September 2010 39
Page 1 and 2: Contents Volume 2, No. 1, September
Page 3 and 4: Letter from the President Samuel B.
Page 5 and 6: News from the Roth Williams Teachin
Page 7 and 8: In addition, three 8-hour courses w
Page 9 and 10: Drs. Edson Illipronti and Solange F
Page 11 and 12: The Transverse Dimension: Diagnosis
Page 13 and 14: Figure 4 Patient with gingival rece
Page 15 and 16: idge determines the width of the ma
Page 17 and 18: Figure 16 MPV of a cone-beam CT sca
Page 19 and 20: 8. Vanarsdall RL. Transverse dimens
Page 21 and 22: Hinge Axis: The Need for Accuracy i
Page 23 and 24: to the flag table (Figure 25). The
Page 25 and 26: The Axi-Path is designed so that th
Page 27 and 28: Figure 43 Nasion relator moves tran
Page 29 and 30: The distance between the preauricul
Page 31 and 32: Figure 63 Flag table. Figure 64 Fla
Page 33 and 34: Figure 72 Figure 73 Supposition: Th
Page 35 and 36: Figure 83 The distance between the
Page 37: Condylar Resorption, Matrix Metallo
Page 41 and 42: shows promise in curbing the bone l
Page 43 and 44: 29. Zardeneta G, Milam SB, Lee T, S
Page 45 and 46: Comparison of Maxillary Cast Positi
Page 47 and 48: points. They found that the mean di
Page 49 and 50: Figure 2-a, b True-hinge facebow. F
Page 51 and 52: to adjust for experimentwide error
Page 53 and 54: pending upon the direction in which
Page 55 and 56: 28. Goska JR, Christensen LV. Compa
Page 57 and 58: The Effect of Tooth Wear on Postort
Page 59 and 60: Figure 4 Slight attrition occurred
Page 61 and 62: improved, with retraction of the up
Page 63 and 64: Figure 9-e Left lateral intraoral p
Page 65 and 66: All available intraoral photographs
Page 67 and 68: Figure 21 Mandibular movement after
Page 69 and 70: Physiologic Treatment Goals in Orth
Page 71 and 72: REFERENCES 1. Dawson PE. The Concep
Page 73 and 74: 70. McNamara JA Jr. The independent
Page 75 and 76: Effect of Gnathologic Positioner We
Page 77 and 78: sure was first checked in the mount
Page 79 and 80: For these analyses, the desired sig
Page 81 and 82: the .05 level of significance in th
Page 83 and 84: RWISO Journal | September 2010 83

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