Literature Review/Book Review
Do matrix metalloproteinases play a role in degenerative disease of temporomandibular joint? A systematic review Lorena Marques Ferreira, A´lvaro Flaviano Benevides Moura, Gustavo Augusto Seabra Barbosa, Hallissa Simplı´cio Gomes Pereira, Patrı´cia dos Santos Calderon Department of Dentistry, Federal University of Rio Grande do Norte, Natal, Brazil Objective: To evaluate whether the high expression of metalloproteinases observed in the temporomandibular joint can be considered as an indicator of degenerative disease. Methods: The PubMed, BVS, Embase, and ScienceDirect databases were systematically searched for articles written in English, regarding human studies that were published from 2003 to 2013. After applying the exclusion and inclusion criteria, four articles were selected. Results: Two studies analyzed the presence of matrix metalloproteinases (MMPs) through histology and immunohistochemical evaluation of articular discs; both observed a higher concentration of MMPs in the discs of ill patients. Another study, using genomic DNA from oral cells of ill and healthy patients, found a higher presence of MMP-1G/2G in affected individuals. A fourth study examined the synovial fluid of patients and control groups and concluded that MMPs were present in most patients with articular changes. Discussion: Despite the lack of methodology standardization, the studies showed a higher presence of MMPs in temporomandibular joint (TMJ) patients with degenerative diseases, indicating a possible marker related to these diseases. However, further studies, with a higher level of evidence and more significant samples, are necessary in order to confirm these findings. Keywords: Matrix metalloproteinases, Temporomandibular joint disorders, Osteoarthritis
Introduction The compressive stress on the synovial cells of the temporomandibular joint (TMJ) appears to modulate the production of inflammatory cytokines such as metalloproteinases (MMPs).1 These proteinases, also termed matrixins, hydrolyze components of the extracellular matrix. They play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, angiogenesis, and in diseases such as atheroma, arthritis, cancer, tissue ulceration and TMJ degenerative disease.2 Currently, 23 MMP genes have been identified in humans, and most are multidomain proteins.3 Their activity is regulated not only at the gene expression
Correspondence to: L. M. Ferreira, Department of Dentistry, Federal University of Rio Grande do Norte, Natal, Brazil, R. Custo´dio da Silva, 367, Condomı´nio Terra da Liberdade, ap. 504A, Santo Antoˆnio, Mossoro´-RN, CEP: 59619-045, Brazil. Email: [email protected] ß W. S. Maney & Son Ltd 2014 DOI 10.1179/2151090314Y.0000000034
level, but is also regulated by inhibitors, including an MMP-specific family, tissue inhibitors of metalloproteinases (TIMPs).4 MMPs are functionally balanced with their tissue inhibitors (TIMPs) during normal metabolism.2 This leads to homeostasis of extracellular matrix and replacement of old or damaged cells. The main characteristic change in degenerative temporomandibular disorders (TMDs) is the alteration of this equilibrium, resulting in excessive degradation of extracellular matrix collagen.5 High activities of diverse MMPs are believed to be highly involved in matrix breakdown.2–4 These cytokines can infiltrate the synovium, which may alter the synovial fluid (SF) viscosity and lead to impairment in the lubrication and nutrition of articular cartilage and disc.6 The identification of the proteins found in TMJ degenerative disease could help identify which proteins can cause pain, disc degeneration, painful clicking, or locking.7
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MMPs play a role in degenerative disease of TMJ
Thus, this study aimed, through a systematic review, to determine whether high expression of MMPs can be considered as an indicator of TMJ degenerative disease. It is important to consider that the identification of a marker in the tissues or fluids of the joint can be considered as a new approach for early diagnosis and therapeutic intervention.
Materials and Methods Search strategy
studies that addressed TMJ degenerative diseases and that allow the evaluation of MMPs in the disease; publications over the last ten years (2003–2013).
4.
The following exclusion criteria were elected: 1. case reports; 2. pilot studies; 3. literature review.
Data analysis
Two reviewers conducted an electronic search, independently, on the PubMed, BVS, Embase, and ScienceDirect Databases, including only articles written in English and published over the past 10 years (2003–2013). The following search strategies were used: 1. (temporomandibular dysfunction* OR temporomandibular disorder* OR joint temporomandibular OR degeneration temporomandibular OR TMJ) AND (metalloproteinase OR matrix metalloproteinase OR MMP*); 2. (osteoarthritis OR rheumatoid arthritis) AND (temporomandibular OR TMJ) AND (metalloproteinase OR matrix metalloproteinase OR MMP*).
After removal of duplicates, all titles revealed were screened, followed by an abstract analysis to find further accordance with the inclusion and exclusion criteria. Considering the abstracts, full-text articles were chosen. A hand search was held to search for potentially relevant articles. Any remaining disagreement concerning the selected articles was solved by discussion.
Selection criteria Studies were eligible for inclusion in the review if they met the following criteria: 1. 2.
3.
English-language publication; human studies;
Data were obtained from all selected articles and included the following parameters: author and year of publication, sample characteristics, mean age of subjects, type of MMP, TMJ assessment, MMP assessment, and main results (Table 1).
Results General outcomes The final electronic search on databases revealed 143 records. After removal of duplicates, 67 articles remained. The inter-reviewer discussion resulted in 28 articles that were screened according to the inclusion and exclusion criteria observing the titles and abstracts. The hand searching revealed four additional studies. In total, 32 articles were fully read (Fig. 1). Of these, 28 were removed, according to the exclusion criteria (Table 2). Finally, this systematic review included four articles. No statistical analysis of data was performed, due to the different study designs. Researches’ characteristics and main results are presented in Table 1.
Description of the studies Leonardi et al.6 evaluated the presence of collagenase-3 (MMP-13), using 10 articular discs of patients, aged 24–52 years, who presented disc derangement associated with pain and who underwent arthroscopy. As controls, two healthy discs were analyzed. The pieces were treated histochemically with antibodies
Table 1 Researches’ characteristics and main result
Author/year
Sample
Age (mean)
MMP
MMP assessment
TMJ assessment
Yoshida et al.,10 2006
G1: 44 samples of synovial fluid from TMD patients G2: 15 controls G1: 10 cases of TMJ arthroscopy G2: Two controls G1: 115 individuals with TMD G2: 117 controls
G1: 36.5 G2: 23.1
MMP-2 MMP-9
Immunoblotting
MRI
MMP-2, MMP-9: G1.G2 (P,0.05)
G1: 43.7 G2: 54
MMP-13
Histology and Immunohistochemical
Unreported
MMP-13: G1.G2 (P,0.01)
G1: 42.82 G2: 38.04
MMP-1 MMP-3 MMP-9
DNA genome (oral epithelial cells)
MRI and CT
G1: 25 discs of patients with TMD G2: Four controls
G1: 34.2 G2: 49.7
MMP-7 MMP-9
Histology and Immunohistochemical
MRI
MMP-1 1G/2G, G1.G2 (P50.03) MMP-3 5A/6A, MMP-9 C/T: G1 5 G2 (P.0.05) MMP-7, MMP-9: G1.G2 (P50.01)
Leonardi et al.,8 2008 Planello et al.,4 2011
Loreto et al.,9 2013
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Figure 1 Flow chart of process of systematic literature search.
for MMP-13, and were subsequently analyzed by three independent researchers who applied the scores of 0–3 to grade conditions from non-reactivity to strong reactivity. Patients in the control group rarely presented immunopositive results for MMP-13, while the discs of patients with TMJ dysfunction resulted in a higher incidence (up to five times higher), depending on the degree of tissue injury. Loreto et al.7 studied the immunohistochemical expression of MMP-7 and MMP-9 in 25 discs from patients with TMJ-internal derangement (ID) and 4 from healthy donors. MPP-7 and MMP-9 staining intensity and the proportion of immunopositive cells found were examined in blind by light microscopy
and recorded by three anatomists. They assigned scores ranging from 0 to 4 to the findings: 0 for no detectable stains and 4 for the strongest staining. The final observations evidenced a greater proportion of cells positive for MMP-7 and MMP-9; the increase was proportional to the severity of the injury. The control discs exhibited faint immunostaining. Planello et al.5 analyzed the frequency of MMP-1 1G/2G polymorphism, MMP-3 5A/6A polymorphism, and MMP-9 C/T polymorphism, using the DNA genome isolated from oral epithelial cells in a sample of 117 healthy subjects and 115 patients with degenerative alterations of the TMJ. Genotypes were determined using PCR restriction fragment length
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Table 2 Articles not selected for systematic review and exclusion criteria
Animal studies (n510) Chen K et al. (2013) Tanimoto K et al. (2011) Ohno S et al. (2005) Wang YL et al. (2013) Xiao D et al. (2012) Embree MC et al. (2010) Jiao K et al. (2013) Shen M et al. (2013) Man C et al. (2009) Milner JM et al. (2006) Literature review (n53) Frisardi G et al. (2010) Schwartz HC (2013) Wu YS et al. (2007) Pilot study (n51) Herr MM et al. (2011)
Does not allow for the evaluation of the influence of MMPs in DJD (n514) Tiilikainen P et al. (2005) Fujita H et al. (2008) Matsumoto T et al. (2008) Song F et al. (2006) Akamine Y et al. (2012) Paegle DI et al. (2005) Paegle DI et al. (2003) Frisardi et al. (2010) Bailey MM et al. (2007) Murai Y et al. (2007) Sambajor VV et al. (2003) Dursun N et al. (2011) Barlas IO et al. (2009) Song F et al. (2005)
polymorphism. The results revealed an association between the MMP1 2G/2G genotype and degeneration; in contrast, there was no association between either the MMP3 or the MMP9 genotype and degeneration. Yoshida et al.10 investigated the presence of MMP2 and MMP-9 in the synovial fluid of 44 joints of patients aged between 17 and 74 years with displaced TMJ disc and osteoarthritis, diagnosed by MRI. Fifteen joints without signs or symptoms of ID of the TMJ were used as the control group. The synovial fluid was collected by puncture into the superior joint space from a posterolateral approach. The results demonstrated that the case group had a MMP-2 and MMP-9 expression significantly higher than the control group.
Discussion This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses system11 in order to find the best available scientific evidence regarding the high expression of MMPs as an indicator of degenerative disease of the TMJ. The initial survey retrieved a significant number of studies on the subject; however, after a careful assessment, it was observed that most of them did not fit the inclusion criteria. Thus, only four studies were included in the present study. The majority of the selected articles had small samples, probably due to the inherent difficulty in obtaining the type of material used. The exception was the study by Planello et al.,5 which was able to assess 232 individuals by collecting cells from oral epithelium. Furthermore, the evaluation methods of these samples were diverse, such as immunohistochemical examination of the articular disc, chemical 4
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tests for identification of proteins in preparation of synovial fluid, and evaluation of genomic DNA in oral mucosa cells, making the interpretation of the results difficult. Three of the four studies analyzed: Leonardi et al.,8 Loreto et al.,9 and Yoshida et al.,10 observed a higher presence of MMPs in the patient group. In addition, Leonardi et al.8 and Loreto et al.9 highlighted that the greater the degree of severity, the greater the number of MMPs detected. However, these two studies have a very small control group, which is a limitation that makes the interpretation of their results difficult. The study by Planello et al.5 found a relationship between MMP-1 and TMJ degeneration, but did not observe significant differences between the case and control groups for MMP-3 and MMP-9. This may have been due to the different assessment method, which used DNA from oral cells instead of disc or synovial fluid specimens. It is important to consider the various types of MMPs surveyed (1, 3, 7, 9, 13), which also leads to difficulties in comparing the results of studies. MMP13 was studied only by Leonardi et al.8 The same thing occurred with the MMP-7 in the study of Loreto.9 MMP-9 were studied by Loreto et al.9, Yoshida et al.,10 and Planello et al.,5 but with different findings among the studies. Planello et al.5 did not find any association between MMP-9 and degenerative diseases. Yoshida et al.10 and Loreto et al.9 found this association, but the study of Loreto9 presents an insignificant control group. MMPs are being widely studied, since they participate in a large number of physiological processes, such as dentin mineralization, tooth eruption, and collagen remodeling in periodontal tissues, among others. In human metabolism, they also participate in pathological processes, such as periodontal tissue destruction, root caries lesions, TMJ disorders, and metastasis.12 These enzymes play an important role in both physiological and pathological conditions. The degree of this involvement can be modulated either by increasing or decreasing MMP expression and activity.9 Therefore, understanding the roles of MMPs and TIMPs may lead to the development of new drug treatments for various disorders based on suppression or upregulation of their expression.4,13 According to Carmeli et al.,13 insights into protein degradation mechanisms induced by MMPs may also indicate potential preventive strategies for retarding structural and physiological deterioration in various pathologies. This knowledge about MMPs can enable their medical and dental use as markers, leading to confirmation of early diagnosis. As the role of MMPs in disease VOL .
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becomes better understood, interest in the control of their activity increases. However, an important question to address is which MMPs are involved in each disease.14 Currently, disease association studies tend to be limited by the lack of appropriate and standardized research tools and by the fact that not all MMPs have been investigated.14 Srinivas et al.15 sought to verify the presence of MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13 in the SF of mild and severe TMJ-ID and to evaluate whether the SF MMPs are potential diagnostic markers that reflect the stage of intra-articular inflammation in the TMJ. Authors concluded that the degradation of type I collagen in the TMJ was evidently due to the collective action of many collagenolytic MMPs present in the SF of patients with mild and severe TMJ-ID. They emphasized that elevated levels of MMP-2, MMP-9, and MMP-8 in the SF of patients with mild TMJ-ID eventually reflected the active phase of TMJ destruction. These observations may have considerable diagnostic and therapeutic significance in the management of TMJ disorders. Despite the significant advances in MMP research, clinical trials on the treatment of TMJ diseases through the inhibition of MMPs have been disappointing. Nevertheless, the potential for an MMP inhibitor with a good pharmacokinetic profile and appropriate MMP selectivity is such that the area will remain of great interest to the pharmaceutical industry. The challenge is to learn more about the complex interaction and balance of MMPs, both in disease states and in maintaining homeostasis, and to generate more structural information for the design of selective inhibitors with improved pharmacokinetic profiles and reduced toxicity.14 Although there are few results on the influence of MMPs in TMJ degenerative diseases, recent studies have addressed the use of already established drugs (such as erythromycin, clarithromycin, azithromycin, and triclosan), and their effect in the metabolism of MMPs in different parts of the body. Hashimoto et al.16 studied the relationship between the concentration of erythromycin and matrix MMP9 activity, and demonstrated that the suppressive effect of erythromycin on MMP-9 activity is one of the anti-inflammatory mechanisms that inhibit the migration of inflammatory cells into the inflammatory site. Kim et al.17 examined the effect of azithromycin on cell proliferation and collagen turnover modified by cyclosporin A. Their results suggested that azithromycin blocks cyclosporine A-induced cell proliferation and collagen synthesis, and activates MMP-2 in
MMPs play a role in degenerative disease of TMJ
gingival fibroblasts of patients with cyclosporine Ainduced gingival overgrowth. Ogawa et al.18 administered clarithromycin to murine cardiac allograft recipients, in order to clarify its effects in cardiac rejection, and observed that the drug suppressed MMP-9 expression in the allografts, resulting in a myocardial inflammatory cell infiltration. The authors concluded that clarithromycin was useful in suppressing allograft rejection. Barnes et al.19 examined the inhibitory effects of triclosan on lipopolysaccharide-, parathyroid hormone-, and prostaglandin E2-induced expression of MMP-13 in an osteoblastic osteosarcoma cell line. The authors identified a nuclear mechanism of action of triclosan that accounts for the inhibited parathyroid hormone- or prostaglandin E2-induced MMP-13 expression in osteoblastic cells. These studies demonstrate that the influence of certain drugs on MMP expression may be an important factor in the control and treatment of patients suffering from various diseases. Finally, the studies included suggest that there is a higher presence of MMPs in TMJ patients with degenerative diseases, indicating a possible marker related to these diseases; however, more studies need to be carried out in this area because this information can make a big difference in early diagnosis and treatment of TMJ degenerative diseases. The studies’ samples analyzed were not standardized regarding their characterization, size, evaluation method, and type of MMP. Therefore, further studies with a higher level of evidence, such as prospective studies, and more representative samples should be conducted in order to validate MMPs as a marker for this disease, or not.
Disclaimer Statements Contributors We certify that all authors have made a significant scientific contribution to the study and we are thoroughly familiar with the primary data outlined in the manuscript. We have read the complete manuscript and take responsibility for the content and completeness of the final submitted manuscript. Funding None. Conflicts of interest We certify that we have no commercial associations (e.g. consultancies, patentlicensing arrangements, equity interests) that might represent a conflict of interest in connection with the submitted manuscript. Ethics approval None.
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References 1 Muroi Y, Kakudo K, Nakata K. Effects of compressive loading on human synovium-derived cells. J Dent Res. 2007;86(8):786– 91. 2 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39. 3 Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–73. 4 Peng WJ, Yan JW, Wan YN, Wang BX, Tao JH, Yang GJ, et al. Matrix Metalloproteinases: a review of their structure and role in systemic sclerosis. J Clin Immunol. 2012;32(6):1409– 1414. 5 Planello AC, Campos MI, Meloto CB, Secolin R, RizattiBarbosa CM, Line SR, et al. Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration. Eur J Oral Sci. 2011;119(1):1–6. 6 Jiang Q, Qiu YT, Chen MJ, Zhang ZY, Yang C. Synovial TGF-b1 and MMP-3 levels and their correlation with the progression of temporomandibular joint osteoarthritis combined with disc displacement: a preliminary study. Biomed Rep. 2013;1(2):218–22. 7 Herr MM, Fries KM, Upton LG, Edsberg LE. Potential biomarkers of TMJ disorders. J Oral Maxillofac Surg. 2011;69(1):41–7. 8 Leonardi R, Loreto C, Barbato E, Caltabiano R, Lombardo C, Musumeci G, et al. MMP-13 (collagenase 3) localization in human temporomandibular joint discs with internal derangement. Acta Histochem. 2008;110(4):314–8. 9 Loreto C, Leonardi R, Musumeci G, Pannone G, Castorina S. An ex vivo study on immunohistochemical localization of MMP-7 and MMP-9 in temporomandibular joint discs with internal derangement. Eur J Histochem. 2013;57(2):e12.
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10 Yoshida K, Takatsuka S, Hatada E, Nakamura H, Tanaka A, Ueki K, et al. Expression of matrix metalloproteinases and aggrecanase in the synovial fluids of patients with symptomatic temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(1):22–7. 11 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 12 Souza AP, Line SR. The biology of matrix metalloproteinases. Rev FOB. 2002;10(1):1–6. 13 Carmeli E, Moas M, Reznick AZ, Coleman R. Matrix metalloproteinases and skeletal muscle: a brief review. Muscle Nerve. 2004;29(2):191–7. 14 Whittaker M, Ayscough A. Matrix metalloproteinases and their inhibitors: current status and future challenges. Celltransmissions. 2001;17(1):3–14. 15 Srinivas R, Sorsa T, Tja¨derhane L, Niemi E, Raustia A, Pernu H, et al. Matrix metalloproteinases in mild and severe temporomandibular joint internal derangement synovial fluid. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91(5):517–25. 16 Hashimoto N, Kawabe T, Hara T, Imaizumi K, Wakayama H, Saito H, et al. Effect of erythromycin on matrix metalloproteinase-9 and cell migration. J Lab Clin Med. 2001;137(3):176–83. 17 Kim JY, Park SH, Cho KS, Kim HJ, Lee CK, Park KK, et al. Mechanism of azithromycin treatment on gingival overgrowth. J Dent Res. 2008;87(11):1075–9. 18 Ogawa M, Suzuki J, Takayama K, Isobe M. Matrix metalloproteinase suppression induced by clarithromycin in murine cardiac allografts. Transplant Proc. 2009;41(1):395–97. 19 Barnes VM, Xu T, Shimizu E, Nakatani T, Jefcoat S, Vasilov A, et al. Triclosan blocks MMP-13 expression in hormonestimulated osteoblasts. J Periodontol. 2013;84(11):1683–9.
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Do matrix metalloproteinases play a role in degenerative disease of temporomandibular joint? A systematic review Lorena Marques Ferreira, A´lvaro Flaviano Benevides Moura, Gustavo Augusto Seabra Barbosa, Hallissa Simplı´cio Gomes Pereira, Patrı´cia dos Santos Calderon Department of Dentistry, Federal University of Rio Grande do Norte, Natal, Brazil Objective: To evaluate whether the high expression of metalloproteinases observed in the temporomandibular joint can be considered as an indicator of degenerative disease. Methods: The PubMed, BVS, Embase, and ScienceDirect databases were systematically searched for articles written in English, regarding human studies that were published from 2003 to 2013. After applying the exclusion and inclusion criteria, four articles were selected. Results: Two studies analyzed the presence of matrix metalloproteinases (MMPs) through histology and immunohistochemical evaluation of articular discs; both observed a higher concentration of MMPs in the discs of ill patients. Another study, using genomic DNA from oral cells of ill and healthy patients, found a higher presence of MMP-1G/2G in affected individuals. A fourth study examined the synovial fluid of patients and control groups and concluded that MMPs were present in most patients with articular changes. Discussion: Despite the lack of methodology standardization, the studies showed a higher presence of MMPs in temporomandibular joint (TMJ) patients with degenerative diseases, indicating a possible marker related to these diseases. However, further studies, with a higher level of evidence and more significant samples, are necessary in order to confirm these findings. Keywords: Matrix metalloproteinases, Temporomandibular joint disorders, Osteoarthritis
Introduction The compressive stress on the synovial cells of the temporomandibular joint (TMJ) appears to modulate the production of inflammatory cytokines such as metalloproteinases (MMPs).1 These proteinases, also termed matrixins, hydrolyze components of the extracellular matrix. They play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, angiogenesis, and in diseases such as atheroma, arthritis, cancer, tissue ulceration and TMJ degenerative disease.2 Currently, 23 MMP genes have been identified in humans, and most are multidomain proteins.3 Their activity is regulated not only at the gene expression
Correspondence to: L. M. Ferreira, Department of Dentistry, Federal University of Rio Grande do Norte, Natal, Brazil, R. Custo´dio da Silva, 367, Condomı´nio Terra da Liberdade, ap. 504A, Santo Antoˆnio, Mossoro´-RN, CEP: 59619-045, Brazil. Email: [email protected] ß W. S. Maney & Son Ltd 2014 DOI 10.1179/2151090314Y.0000000034
level, but is also regulated by inhibitors, including an MMP-specific family, tissue inhibitors of metalloproteinases (TIMPs).4 MMPs are functionally balanced with their tissue inhibitors (TIMPs) during normal metabolism.2 This leads to homeostasis of extracellular matrix and replacement of old or damaged cells. The main characteristic change in degenerative temporomandibular disorders (TMDs) is the alteration of this equilibrium, resulting in excessive degradation of extracellular matrix collagen.5 High activities of diverse MMPs are believed to be highly involved in matrix breakdown.2–4 These cytokines can infiltrate the synovium, which may alter the synovial fluid (SF) viscosity and lead to impairment in the lubrication and nutrition of articular cartilage and disc.6 The identification of the proteins found in TMJ degenerative disease could help identify which proteins can cause pain, disc degeneration, painful clicking, or locking.7
CRANIOH: The Journal of Craniomandibular & Sleep Practice
2014
VOL.
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NO.
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1
Ferreira et al.
MMPs play a role in degenerative disease of TMJ
Thus, this study aimed, through a systematic review, to determine whether high expression of MMPs can be considered as an indicator of TMJ degenerative disease. It is important to consider that the identification of a marker in the tissues or fluids of the joint can be considered as a new approach for early diagnosis and therapeutic intervention.
Materials and Methods Search strategy
studies that addressed TMJ degenerative diseases and that allow the evaluation of MMPs in the disease; publications over the last ten years (2003–2013).
4.
The following exclusion criteria were elected: 1. case reports; 2. pilot studies; 3. literature review.
Data analysis
Two reviewers conducted an electronic search, independently, on the PubMed, BVS, Embase, and ScienceDirect Databases, including only articles written in English and published over the past 10 years (2003–2013). The following search strategies were used: 1. (temporomandibular dysfunction* OR temporomandibular disorder* OR joint temporomandibular OR degeneration temporomandibular OR TMJ) AND (metalloproteinase OR matrix metalloproteinase OR MMP*); 2. (osteoarthritis OR rheumatoid arthritis) AND (temporomandibular OR TMJ) AND (metalloproteinase OR matrix metalloproteinase OR MMP*).
After removal of duplicates, all titles revealed were screened, followed by an abstract analysis to find further accordance with the inclusion and exclusion criteria. Considering the abstracts, full-text articles were chosen. A hand search was held to search for potentially relevant articles. Any remaining disagreement concerning the selected articles was solved by discussion.
Selection criteria Studies were eligible for inclusion in the review if they met the following criteria: 1. 2.
3.
English-language publication; human studies;
Data were obtained from all selected articles and included the following parameters: author and year of publication, sample characteristics, mean age of subjects, type of MMP, TMJ assessment, MMP assessment, and main results (Table 1).
Results General outcomes The final electronic search on databases revealed 143 records. After removal of duplicates, 67 articles remained. The inter-reviewer discussion resulted in 28 articles that were screened according to the inclusion and exclusion criteria observing the titles and abstracts. The hand searching revealed four additional studies. In total, 32 articles were fully read (Fig. 1). Of these, 28 were removed, according to the exclusion criteria (Table 2). Finally, this systematic review included four articles. No statistical analysis of data was performed, due to the different study designs. Researches’ characteristics and main results are presented in Table 1.
Description of the studies Leonardi et al.6 evaluated the presence of collagenase-3 (MMP-13), using 10 articular discs of patients, aged 24–52 years, who presented disc derangement associated with pain and who underwent arthroscopy. As controls, two healthy discs were analyzed. The pieces were treated histochemically with antibodies
Table 1 Researches’ characteristics and main result
Author/year
Sample
Age (mean)
MMP
MMP assessment
TMJ assessment
Yoshida et al.,10 2006
G1: 44 samples of synovial fluid from TMD patients G2: 15 controls G1: 10 cases of TMJ arthroscopy G2: Two controls G1: 115 individuals with TMD G2: 117 controls
G1: 36.5 G2: 23.1
MMP-2 MMP-9
Immunoblotting
MRI
MMP-2, MMP-9: G1.G2 (P,0.05)
G1: 43.7 G2: 54
MMP-13
Histology and Immunohistochemical
Unreported
MMP-13: G1.G2 (P,0.01)
G1: 42.82 G2: 38.04
MMP-1 MMP-3 MMP-9
DNA genome (oral epithelial cells)
MRI and CT
G1: 25 discs of patients with TMD G2: Four controls
G1: 34.2 G2: 49.7
MMP-7 MMP-9
Histology and Immunohistochemical
MRI
MMP-1 1G/2G, G1.G2 (P50.03) MMP-3 5A/6A, MMP-9 C/T: G1 5 G2 (P.0.05) MMP-7, MMP-9: G1.G2 (P50.01)
Leonardi et al.,8 2008 Planello et al.,4 2011
Loreto et al.,9 2013
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Figure 1 Flow chart of process of systematic literature search.
for MMP-13, and were subsequently analyzed by three independent researchers who applied the scores of 0–3 to grade conditions from non-reactivity to strong reactivity. Patients in the control group rarely presented immunopositive results for MMP-13, while the discs of patients with TMJ dysfunction resulted in a higher incidence (up to five times higher), depending on the degree of tissue injury. Loreto et al.7 studied the immunohistochemical expression of MMP-7 and MMP-9 in 25 discs from patients with TMJ-internal derangement (ID) and 4 from healthy donors. MPP-7 and MMP-9 staining intensity and the proportion of immunopositive cells found were examined in blind by light microscopy
and recorded by three anatomists. They assigned scores ranging from 0 to 4 to the findings: 0 for no detectable stains and 4 for the strongest staining. The final observations evidenced a greater proportion of cells positive for MMP-7 and MMP-9; the increase was proportional to the severity of the injury. The control discs exhibited faint immunostaining. Planello et al.5 analyzed the frequency of MMP-1 1G/2G polymorphism, MMP-3 5A/6A polymorphism, and MMP-9 C/T polymorphism, using the DNA genome isolated from oral epithelial cells in a sample of 117 healthy subjects and 115 patients with degenerative alterations of the TMJ. Genotypes were determined using PCR restriction fragment length
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Table 2 Articles not selected for systematic review and exclusion criteria
Animal studies (n510) Chen K et al. (2013) Tanimoto K et al. (2011) Ohno S et al. (2005) Wang YL et al. (2013) Xiao D et al. (2012) Embree MC et al. (2010) Jiao K et al. (2013) Shen M et al. (2013) Man C et al. (2009) Milner JM et al. (2006) Literature review (n53) Frisardi G et al. (2010) Schwartz HC (2013) Wu YS et al. (2007) Pilot study (n51) Herr MM et al. (2011)
Does not allow for the evaluation of the influence of MMPs in DJD (n514) Tiilikainen P et al. (2005) Fujita H et al. (2008) Matsumoto T et al. (2008) Song F et al. (2006) Akamine Y et al. (2012) Paegle DI et al. (2005) Paegle DI et al. (2003) Frisardi et al. (2010) Bailey MM et al. (2007) Murai Y et al. (2007) Sambajor VV et al. (2003) Dursun N et al. (2011) Barlas IO et al. (2009) Song F et al. (2005)
polymorphism. The results revealed an association between the MMP1 2G/2G genotype and degeneration; in contrast, there was no association between either the MMP3 or the MMP9 genotype and degeneration. Yoshida et al.10 investigated the presence of MMP2 and MMP-9 in the synovial fluid of 44 joints of patients aged between 17 and 74 years with displaced TMJ disc and osteoarthritis, diagnosed by MRI. Fifteen joints without signs or symptoms of ID of the TMJ were used as the control group. The synovial fluid was collected by puncture into the superior joint space from a posterolateral approach. The results demonstrated that the case group had a MMP-2 and MMP-9 expression significantly higher than the control group.
Discussion This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses system11 in order to find the best available scientific evidence regarding the high expression of MMPs as an indicator of degenerative disease of the TMJ. The initial survey retrieved a significant number of studies on the subject; however, after a careful assessment, it was observed that most of them did not fit the inclusion criteria. Thus, only four studies were included in the present study. The majority of the selected articles had small samples, probably due to the inherent difficulty in obtaining the type of material used. The exception was the study by Planello et al.,5 which was able to assess 232 individuals by collecting cells from oral epithelium. Furthermore, the evaluation methods of these samples were diverse, such as immunohistochemical examination of the articular disc, chemical 4
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tests for identification of proteins in preparation of synovial fluid, and evaluation of genomic DNA in oral mucosa cells, making the interpretation of the results difficult. Three of the four studies analyzed: Leonardi et al.,8 Loreto et al.,9 and Yoshida et al.,10 observed a higher presence of MMPs in the patient group. In addition, Leonardi et al.8 and Loreto et al.9 highlighted that the greater the degree of severity, the greater the number of MMPs detected. However, these two studies have a very small control group, which is a limitation that makes the interpretation of their results difficult. The study by Planello et al.5 found a relationship between MMP-1 and TMJ degeneration, but did not observe significant differences between the case and control groups for MMP-3 and MMP-9. This may have been due to the different assessment method, which used DNA from oral cells instead of disc or synovial fluid specimens. It is important to consider the various types of MMPs surveyed (1, 3, 7, 9, 13), which also leads to difficulties in comparing the results of studies. MMP13 was studied only by Leonardi et al.8 The same thing occurred with the MMP-7 in the study of Loreto.9 MMP-9 were studied by Loreto et al.9, Yoshida et al.,10 and Planello et al.,5 but with different findings among the studies. Planello et al.5 did not find any association between MMP-9 and degenerative diseases. Yoshida et al.10 and Loreto et al.9 found this association, but the study of Loreto9 presents an insignificant control group. MMPs are being widely studied, since they participate in a large number of physiological processes, such as dentin mineralization, tooth eruption, and collagen remodeling in periodontal tissues, among others. In human metabolism, they also participate in pathological processes, such as periodontal tissue destruction, root caries lesions, TMJ disorders, and metastasis.12 These enzymes play an important role in both physiological and pathological conditions. The degree of this involvement can be modulated either by increasing or decreasing MMP expression and activity.9 Therefore, understanding the roles of MMPs and TIMPs may lead to the development of new drug treatments for various disorders based on suppression or upregulation of their expression.4,13 According to Carmeli et al.,13 insights into protein degradation mechanisms induced by MMPs may also indicate potential preventive strategies for retarding structural and physiological deterioration in various pathologies. This knowledge about MMPs can enable their medical and dental use as markers, leading to confirmation of early diagnosis. As the role of MMPs in disease VOL .
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becomes better understood, interest in the control of their activity increases. However, an important question to address is which MMPs are involved in each disease.14 Currently, disease association studies tend to be limited by the lack of appropriate and standardized research tools and by the fact that not all MMPs have been investigated.14 Srinivas et al.15 sought to verify the presence of MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13 in the SF of mild and severe TMJ-ID and to evaluate whether the SF MMPs are potential diagnostic markers that reflect the stage of intra-articular inflammation in the TMJ. Authors concluded that the degradation of type I collagen in the TMJ was evidently due to the collective action of many collagenolytic MMPs present in the SF of patients with mild and severe TMJ-ID. They emphasized that elevated levels of MMP-2, MMP-9, and MMP-8 in the SF of patients with mild TMJ-ID eventually reflected the active phase of TMJ destruction. These observations may have considerable diagnostic and therapeutic significance in the management of TMJ disorders. Despite the significant advances in MMP research, clinical trials on the treatment of TMJ diseases through the inhibition of MMPs have been disappointing. Nevertheless, the potential for an MMP inhibitor with a good pharmacokinetic profile and appropriate MMP selectivity is such that the area will remain of great interest to the pharmaceutical industry. The challenge is to learn more about the complex interaction and balance of MMPs, both in disease states and in maintaining homeostasis, and to generate more structural information for the design of selective inhibitors with improved pharmacokinetic profiles and reduced toxicity.14 Although there are few results on the influence of MMPs in TMJ degenerative diseases, recent studies have addressed the use of already established drugs (such as erythromycin, clarithromycin, azithromycin, and triclosan), and their effect in the metabolism of MMPs in different parts of the body. Hashimoto et al.16 studied the relationship between the concentration of erythromycin and matrix MMP9 activity, and demonstrated that the suppressive effect of erythromycin on MMP-9 activity is one of the anti-inflammatory mechanisms that inhibit the migration of inflammatory cells into the inflammatory site. Kim et al.17 examined the effect of azithromycin on cell proliferation and collagen turnover modified by cyclosporin A. Their results suggested that azithromycin blocks cyclosporine A-induced cell proliferation and collagen synthesis, and activates MMP-2 in
MMPs play a role in degenerative disease of TMJ
gingival fibroblasts of patients with cyclosporine Ainduced gingival overgrowth. Ogawa et al.18 administered clarithromycin to murine cardiac allograft recipients, in order to clarify its effects in cardiac rejection, and observed that the drug suppressed MMP-9 expression in the allografts, resulting in a myocardial inflammatory cell infiltration. The authors concluded that clarithromycin was useful in suppressing allograft rejection. Barnes et al.19 examined the inhibitory effects of triclosan on lipopolysaccharide-, parathyroid hormone-, and prostaglandin E2-induced expression of MMP-13 in an osteoblastic osteosarcoma cell line. The authors identified a nuclear mechanism of action of triclosan that accounts for the inhibited parathyroid hormone- or prostaglandin E2-induced MMP-13 expression in osteoblastic cells. These studies demonstrate that the influence of certain drugs on MMP expression may be an important factor in the control and treatment of patients suffering from various diseases. Finally, the studies included suggest that there is a higher presence of MMPs in TMJ patients with degenerative diseases, indicating a possible marker related to these diseases; however, more studies need to be carried out in this area because this information can make a big difference in early diagnosis and treatment of TMJ degenerative diseases. The studies’ samples analyzed were not standardized regarding their characterization, size, evaluation method, and type of MMP. Therefore, further studies with a higher level of evidence, such as prospective studies, and more representative samples should be conducted in order to validate MMPs as a marker for this disease, or not.
Disclaimer Statements Contributors We certify that all authors have made a significant scientific contribution to the study and we are thoroughly familiar with the primary data outlined in the manuscript. We have read the complete manuscript and take responsibility for the content and completeness of the final submitted manuscript. Funding None. Conflicts of interest We certify that we have no commercial associations (e.g. consultancies, patentlicensing arrangements, equity interests) that might represent a conflict of interest in connection with the submitted manuscript. Ethics approval None.
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References 1 Muroi Y, Kakudo K, Nakata K. Effects of compressive loading on human synovium-derived cells. J Dent Res. 2007;86(8):786– 91. 2 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39. 3 Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–73. 4 Peng WJ, Yan JW, Wan YN, Wang BX, Tao JH, Yang GJ, et al. Matrix Metalloproteinases: a review of their structure and role in systemic sclerosis. J Clin Immunol. 2012;32(6):1409– 1414. 5 Planello AC, Campos MI, Meloto CB, Secolin R, RizattiBarbosa CM, Line SR, et al. Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration. Eur J Oral Sci. 2011;119(1):1–6. 6 Jiang Q, Qiu YT, Chen MJ, Zhang ZY, Yang C. Synovial TGF-b1 and MMP-3 levels and their correlation with the progression of temporomandibular joint osteoarthritis combined with disc displacement: a preliminary study. Biomed Rep. 2013;1(2):218–22. 7 Herr MM, Fries KM, Upton LG, Edsberg LE. Potential biomarkers of TMJ disorders. J Oral Maxillofac Surg. 2011;69(1):41–7. 8 Leonardi R, Loreto C, Barbato E, Caltabiano R, Lombardo C, Musumeci G, et al. MMP-13 (collagenase 3) localization in human temporomandibular joint discs with internal derangement. Acta Histochem. 2008;110(4):314–8. 9 Loreto C, Leonardi R, Musumeci G, Pannone G, Castorina S. An ex vivo study on immunohistochemical localization of MMP-7 and MMP-9 in temporomandibular joint discs with internal derangement. Eur J Histochem. 2013;57(2):e12.
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10 Yoshida K, Takatsuka S, Hatada E, Nakamura H, Tanaka A, Ueki K, et al. Expression of matrix metalloproteinases and aggrecanase in the synovial fluids of patients with symptomatic temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(1):22–7. 11 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 12 Souza AP, Line SR. The biology of matrix metalloproteinases. Rev FOB. 2002;10(1):1–6. 13 Carmeli E, Moas M, Reznick AZ, Coleman R. Matrix metalloproteinases and skeletal muscle: a brief review. Muscle Nerve. 2004;29(2):191–7. 14 Whittaker M, Ayscough A. Matrix metalloproteinases and their inhibitors: current status and future challenges. Celltransmissions. 2001;17(1):3–14. 15 Srinivas R, Sorsa T, Tja¨derhane L, Niemi E, Raustia A, Pernu H, et al. Matrix metalloproteinases in mild and severe temporomandibular joint internal derangement synovial fluid. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;91(5):517–25. 16 Hashimoto N, Kawabe T, Hara T, Imaizumi K, Wakayama H, Saito H, et al. Effect of erythromycin on matrix metalloproteinase-9 and cell migration. J Lab Clin Med. 2001;137(3):176–83. 17 Kim JY, Park SH, Cho KS, Kim HJ, Lee CK, Park KK, et al. Mechanism of azithromycin treatment on gingival overgrowth. J Dent Res. 2008;87(11):1075–9. 18 Ogawa M, Suzuki J, Takayama K, Isobe M. Matrix metalloproteinase suppression induced by clarithromycin in murine cardiac allografts. Transplant Proc. 2009;41(1):395–97. 19 Barnes VM, Xu T, Shimizu E, Nakatani T, Jefcoat S, Vasilov A, et al. Triclosan blocks MMP-13 expression in hormonestimulated osteoblasts. J Periodontol. 2013;84(11):1683–9.
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