Abstract
Osteoarthritis (OA) is a slow progressing degenerative disease that affects the joints, including the temporomandibular joint. In the present study, transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase 3 (MMP-3) in synovial fluid (SF) were examined in detecting cartilage synthesis and degradation in progression of temporomandibular joint osteoarthritis (TMJ OA) combined with disc displacement (DD) diseases. SF was obtained from 16 patients with TMJ OA combined with DD and 10 normal volunteers. TGF-β1 and MMP-3 levels were measured by enzyme-linked immunosorbent assay. In addition, TMJ OA combined with DD was classified into three stages based on radiographic signs on the preoperative tomograms and surgical findings at operation, and different treatment options were administered according to the stages. SF from TMJs with TMJ OA combined with DD showed higher levels of TGF-β1 and MMP-3 compared with the asymptomatic control TMJs. With the progression of TMJ OA combined with DD, TGF-β1 levels in SF were lower, while MMP-3 levels in SF were significantly higher. In conclusion, these data suggest that MMP-3 is not only involved in the pathological destruction process of TMJ OA combined with DD initially, but also has a positive correlation with the degree of pathological changes. Furthermore, a significant increase of TGF-β1 levels was found in the SF that were able to counteract the deleterious effects of MMP-3 at the early stage of TMJ OA combined DD, providing the scientific basis on repositioning displaced disc as early as possible for these patients.
Keywords: temporomandibular joint, osteoarthritis, transforming growth factor-β1, matrix metalloproteinase 3, synovial fluid, opening disc displacement
Introduction
Osteoarthritis (OA) is a slow progressing degenerative disease characterized by cartilage damage, synovial fibrosis and osteophyte formation which may involve several joints, including the temporomandibular joint (TMJ) (1,2). Once the TMJ is involved, severe handicap and significant pain generally occur. Clinically, temporomandibular joint osteoarthritis (TMJ OA) is characterized by joint pain, crepitus, restricted motion and eventually loss of joint function (1–3).
Recent advances in imaging, particularly magnetic resonance imaging (MRI) and arthroscopy have contributed greatly to the understanding of the intra-articular lesions of the disc and condyle (4,5). Pathological changes, such as disc displacement (DD) may be involved in the development of TMJ OA. In their studies, Macher et al (6) and Ali et al (7) demonstrated that the surgical induction of anterior DD in rabbits might lead to OA. Long et al (8) showed that the degree of anterior DD of TMJ is correlated with OA in rabbits. However, a correlation between the change and detailed pathogenesis remains to be adequately elucidated.
Transforming growth factor-β1 (TGF-β1) is an important inducer of cartilage extracellular matrix (ECM) production and is suggested to be a potential tool to enhance cartilage repair upon damage in OA (9–11). By contrast, matrix metalloproteinases (MMPs) are a large group of matrix degrading enzymes that contribute to joint destruction in OA. High activities of diverse MMPs, especially of MMP-3 are believed to be highly involved in matrix breakdown (12–14). 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.
The aim of the present study was to investigate the levels of TGF-β1 and MMP-3 in SF to evaluate the initiation and progression of TMJ OA combined with DD and provide a scientific basis for the assessment of treatment effectiveness for these patients.
Patients and methods
Patients
Consecutive patients referred to our department and who had been selected for TMJ surgical treatment were studied. Patients with inflammation or arthritic diseases other than osteoarthritis and patients who had had traumatic events were excluded. The criteria for surgical treatment were unsuccessful non-surgical treatment and a clinical diagnosis of TMJ OA. The surgical technique has been thoroughly described elsewhere (15–17). The inclusion criteria for TMJ OA combined DD staging were a painful impaired TMJ mobility, radiographic signs on the preoperative tomograms and surgical findings at operation (Table I, Fig. 1). The mean age for these patients was 36.75 years (range, 18–58). There were 15 females and 1 male with a mean duration of symptom of 1.6 years (range, 4 months–5 years) (Table II). The present study was approved by the ethics committee of Shanghai Ninth People’s Hospital affiliated to Shanghai JiaoTong University, School of Medicine. Informed consent and written agreement was obtained from each patient.
Table I.
Staging of TMJ OA combined with DD.
| Staging (TMJ OA combined with DD) | Imaging findings | Surgical findings |
|---|---|---|
| Early | Anterior disc displacement, disc deformed moderate to marked disc thickening, abnormal bone contours | Disc deformed disc displaced anteriorly, variable adhesion |
| Intermediate | Anterior disc displacement, Disc deformed, Marked disc thickening, Abnormal bone contours | Degenerative remodeling of condylar cartilage surface, Adhesion, deformed disc without perforation |
| Late | Anterior disc displacement with disc perforation, Disc deformed badly, Degenerative osseous changes | Gross degenerative changes of disc and hard tissue, Disc perforation, Multiple adhesion |
TMJ OA, temporomandibular joint osteoarthritis; DD, disc displacement.
Figure 1.
Magnetic resonance imaging (MRI) of temporo mandibular joint osteoarthritis (TMJ OA) combined with disc displacement (DD) is shown. (A and B) showed early TMJ OA combined with DD; (C) and (D) showed intermediate TMJ OA combined DD; (E and F) showed late TMJ OA combined with DD; (A, C and E) closed position; (B, D and F) open position. Green arrow, disc perforation.
Table II.
Patient characteristics.
| No. | Gender | Age (years) | Staging | Surgical treatment |
|---|---|---|---|---|
| 1 | Female | 20 | Intermediate | Open disc repositioning |
| 2 | Female | 50 | Late | Shave the osteophyte combined with open disc repositioning |
| 3 | Female | 53 | Intermediate | Open disc repositioning |
| 4 | Female | 21 | Early | Open disc repositioning |
| 5 | Male | 53 | Late | Condylectomy and reconstruction with costochondral graft |
| 6 | Female | 58 | Early | Open disc repositioning |
| 7 | Female | 52 | Late | Shave the osteophyte combined with open disc repositioning |
| 8 | Female | 18 | Late | Condylectomy and reconstruction with costochondral graft |
| 9 | Female | 28 | Intermediate | Open disc repositioning |
| 10 | Female | 22 | Late | Open disc repositioning |
| 11 | Female | 25 | Intermediate | Open disc repositioning |
| 12 | Female | 43 | Late | Condylectomy and reconstruction with costochondral graft |
| 13 | Female | 23 | Early | Open disc repositioning |
| 14 | Female | 51 | Intermediate | Open disc repositioning |
| 15 | Female | 51 | Intermediate | Open disc repositioning |
| 16 | Female | 20 | Early | Open disc repositioning |
SF samples from TMJ
The experimental SFs were collected from >16 patients during surgery. The control SFs were collected from 10 healthy check-up examinees with no clinical and radiological evidence of TMJ OA. The TMJ was punctured with a standard disposable needle (diameter of 0.65 mm) inserted into the posterior part of the upper joint compartment. TMJ SF samples were obtained by washing the joint cavity with saline using the push and pull technique. SFs were then centrifuged for 20 min at 2,000 x g using serum monovettes (Sarstedt, Nümbrecht, Germany) and stored at −80°C until use.
Enzyme-linked immunosorbent assay (ELISA)
Commercially available human DuoSet ELISAs (R&D Systems, Inc., Minneapolis, MN, USA) were used to estimate the concentrations of TGF-β1 and MMP-3 in appropriately diluted SFs. Ninety-six-well flat plates were coated overnight with the primary antibody at room temperature (HCl 1 N) for 10 min, following reneutralization (NaOH 2.7 N/HEPES 1 M). Samples and controls of known concentration were added in wells for 2 h and were incubated with the secondary antibody for an additional 2 h. Conjugation with horseradish peroxidase and addition of tetramethylbenzidine and H2O2 produced light emission at 450 nm. Results were corrected by subtraction of light emission at an aborbance value of 540 nm.
Statistical analysis
Data were presented as the mean ± standard error of the mean. The Statistical Package for Social Science (SPSS) software version 11.5 (SPSS, Inc, Chicago, IL, USA) was used for statistical processing. The non-parametric Mann-Whitney U Test was used. P<0.05 was considered to indicate a statistically significant difference.
Results
TGF-β1 levels in SF
The median value of TGF-β1 in SF was three times higher when comparing patients with TMJ OA combined with DD to the healthy volunteers. (391.0205 pg/ml vs. 121.6628 pg/ml, P=0.000, z=−4.217) (Table III).
Table III.
TGF-β1 levels in synovial fluid of TMJ OA combined with DD in patients and healthy volunteers.
| Group | Cases | TGF-β1 (pg/ml) |
|---|---|---|
| Control | 10 | 121.6628±15.20046 |
| TMJ OA combined DDa | 16 | 391.0205±130.6354 |
P<0.05. TGF-β1, transforming growth factor-β1; TMJ OA, temporomandibular joint osteoarthritis; DD, disc displacement.
Of the patients, 4 had TMJ OA combined with DD of early staging, 6 had TMJ OA combined with DD of intermediate staging and 6 had TMJ OA combined with DD of late staging (Table II). Notably, the SF from patients with TMJ OA combined with DD of late staging had lower TGF-β1 levels compared with patients of early or intermediate staging (Fig. 2).
Figure 2.
Transforming growth factor-β1 (TGF-β1) levels in synovial fluid from patients with temporomandibular joint osteoarthritis (TMJ OA) combined with disc displacement (DD) of varying staging are shown.
MMP-3 levels in SF
The median value of MMP-3 in SF was six times higher when comparing patients with TMJ OA combined with DD to the healthy volunteers (4047.418 pg/ml vs. 660.3411 pg/ml, P=0.000, z=−4.216) (Table IV).
Table IV.
MMP-3 levels in synovial fluids of TMJ OA combined with DD in patients and healthy volunteers.
| Group | Cases | MMP-3 (pg/ml) |
|---|---|---|
| Control | 10 | 660.3411±110.9955 |
| TMJ OA combined DDa | 16 | 4074.418±933.0046 |
P<0.05. MMP-3, matrix metalloproteinase 3; TMJ OA, temporomandibular joint osteoarthritis; DD, disc displacement.
Moreover, SF from patients with TMJ OA combined with DD of early staging had lower MMP-3 levels compared with patients of intermediate or late staging (Fig. 3).
Figure 3.
Matrix metalloproteinase 3 (MMP-3) levels in synovial fluid from patients with temporomandibular joint osteoarthritis (TMJ OA) combined with disc displacement (DD) of varying staging are shown.
Discussion
SF produced by TMJ synovium normally functions as a biological lubricant as well as a biochemical pool through which nutrients and regulatory cytokines traverse (18,19). The cytokines are secreted by chondrocytes in articular cartilage and synoviocytes in synovium and concentrated in the synovial space by the semi-permeable synovial lining (20,21). Synovial membrane permeability can be altered by inflammation, which produces diseased SF because of alterations to biochemical mediators. Therefore, measuring the change of cytokines in TMJ may contribute to understanding the disease process of TMJ OA combined with DD.
The present study has shown that TGF-β1 and MMP-3 in SF are potential markers in assessing microenviroment inflammation or cartilage change in TMJ OA combined with DD. TGF-β1 is mainly released by articular chondrocytes in TMJ and secreted as an inactive complex comprising a TGF-β1 dimer, its propeptide latency-associated peptide (22). Active TGF-β1 stimulates chondrocytes responding with ECM synthesis from cartilage (23,24) and stabilizes the phenotype of the prehypertrophic chondrocytes (25,26). MMP-3 is secreted from synoviocytes and articular chondrocytes in a latent form, and binds with the tissue inhibitor of the metalloproteinase. MMP-3 is reported to crucial in matrix breakdown since it is capable of degrading a number of cartilage components, including proteoglycan, fibronection and collagens (12–14). Thus, in normal TMJ, small quantities of active TGF-β1 and MMP-3 are well-known in the development and homeostasis of cartilage and bone tissues (27–29).
At the initial stage of TMJ OA combined DD, TGF-β1 and MMP-3 levels in SF were increased while the destruction of bone and cartilage was not evident, which manifested as a reparative response at an early stage. Previous studies have shown TGF-β1 to be an important anabolic with proven beneficial effects on cartilage repair in the initiation of OA (30–32). In their study, van der Kraan et al (10) have demonstrated that an upregulated expression of TGF-β1 in early OA is found to be accompanied by increased synthetic activity. Blaney et al (31) have shown that TGF-β stimulates ECM, and counteracts the main catabolic roles at the early stage of murine knee joints OA. Takahashi et al (32) show that TGF-β1 counteracts the interleukin-1 (IL-1) upregulation of MMPs.
In the process of TMJ OA combined with DD, MMP-3 concentrations in SF were higher while TGF-β1 concentrations in SF showed a gradual decrease. MMP gene expression can be enhanced by pro-inflammatory cytokines, such as IL-1 and tumor necrosis factor-α (TNF-α) (33). Previous studies have shown a high prevalence of synovial inflammation in TMJ OA (34,35). Therefore, with the progression of TMJ OA combined DD, MMP-3 may be activated, while an excessive amount of active MMP-3 directly degrades the cartilage matrix. In addition, MMP-3 is able to activate other MMPs, such as MMP-1, MMP-7 and MMP-9. Thus, a significant increase of MMP-3 was not counteracted by insufficient amounts of TGF-β1, which aggravates the destruction of cartilage that results in the release of osteoclasia of cartilage and TMJ disc perforation.
Therefore, TMJ OA combined with DD is not considered to be a simple and unavoidable result of wear and tear, and sustaining or even enhancing the initial process may be an option. In our study, DD on MRI was observed in the 12 patients. This obvious change in TMJ anatomical structure may affect the homeostasis of joint cartilage. Thus, TMJ open disc repositioning procedures were performed on the 10 patients in the early and intermediate stages of TMJ OA, as well as another 2 patients in the late stage of TMJ OA combined DD, who had small disc perforation. Postoperative MRIs after three or six months showed that: i) the displaced disc was placed in its normal anatomical location; ii) preoperative degenerative changes did not exhibit any evident further development. Moreover, physiological remodeling, such as new bone formation was observed. These findings suggest that the displaced disc should be repositioned as early as possible in patients with TMJ OA combined with DD, in order that the aggravation of OA might be terminated and good condylar remodeling be achieved after disc repositioning, since sufficient amounts of TGF-β1 may be able to counteract the destructive effects of MMP-3 at an early stage.
To elucidate the cause of TMJ OA combined with DD, further investigation regarding the regulatory mechanism of TGF-β1 and MMP-3 in pre- and postoperative periods is required in animals and humans.
Acknowledgments
The present study was supported by a grant from the Natural Science Foundation of China (Grant no. 81070848).
References
- 1.Hawker GA, Mian S, Bednis K, Stanaitis I. Osteoarthritis year 2010 in review: pathomechnisms. Osteoarthritis Cartilage. 2011;19:366–374. doi: 10.1016/j.joca.2011.01.021. [DOI] [PubMed] [Google Scholar]
- 2.Loeser SF. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin Geriatr Med. 2010;26:371–386. doi: 10.1016/j.cger.2010.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rando C, Waldron T. TMJ osteoarthritis: a new approach to diagnosis. Am J Phys Anthropol. 2012;148:45–53. doi: 10.1002/ajpa.22039. [DOI] [PubMed] [Google Scholar]
- 4.Ishimaru JI, Oguma Y, Goss AN. Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and lavage synovial fluid of patients with temporomandibular joint disorders. Br J Oral Maxillofac Surg. 2000;38:354–359. doi: 10.1054/bjom.2000.0306. [DOI] [PubMed] [Google Scholar]
- 5.Ogura I, Kaneda T, Mori S, Sakayanagi M, Kato M. Magnetic resonance characteristics of temporomandibular joint disc displacement in elderly patients. Dentomaxillofac Radiol. 2012;41:122–125. doi: 10.1259/dmfr/1286942. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Macher DJ, Westesson PL, Broks SL, Hicks DG, Tallents RH. Temporomandibular joint: surgically created disk displacement causes arthrosis in the rabbit. Oral Surg Oral Med Oral Pathol. 1992;73:645–649. doi: 10.1016/0030-4220(92)90001-7. [DOI] [PubMed] [Google Scholar]
- 7.Ali AM, Sharawy M. Enlargement of the rabbit mandibular condyle after experimental induction of anterior disc displacement: a histomorphometric study. J Oral Maxillofac Surg. 1995;53:544–560. doi: 10.1016/0278-2391(95)90068-3. [DOI] [PubMed] [Google Scholar]
- 8.Long X, Li JR, Chen X. Evaluation in the relationship of disc displacement of temporomandibular joint to osteoarthrosis in the rabbit. Chin J Stomatol. 1998;33:264–266. (In Chinese) [PubMed] [Google Scholar]
- 9.Tanimoto K, Suzuki A, Ohno S, Honda K, Tanaka N, Doi T, et al. Effects of TGF-beta on hyaluronan anabolism in fibroblasts derived from the synovial membrane of the rabbit temporomandibular joint. J Dent Res. 2004;83:40–44. doi: 10.1177/154405910408300108. [DOI] [PubMed] [Google Scholar]
- 10.van der Kraan PM, Blaney Davidson EN, van den Berg WB. A role for age-related changes in TGF beta signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res Ther. 2010;12:201–209. doi: 10.1186/ar2896. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Baugé C, Girard N, Leclercq S, Galéra P, Boumédiene K. Regulatory mechanism of transforming growth factor beta receptor type II degradation by interleukin-1 in primary chondrocytes. Biochim Biophys Acta. 2012;1823:983–986. doi: 10.1016/j.bbamcr.2012.02.017. [DOI] [PubMed] [Google Scholar]
- 12.Hegemann N, Wondimu A, Ullrich K, Schmidt MF. Synovial MMP-3 and TIMP-1 levels and their correlation with cytokine expression in canine rheumatoid arthritis. Vet Immunol Immunopathol. 2003;91:199–204. doi: 10.1016/s0165-2427(03)00005-9. [DOI] [PubMed] [Google Scholar]
- 13.Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum. 2001;44:585–594. doi: 10.1002/1529-0131(200103)44:3<585::AID-ANR107>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
- 14.Kubota E, Kubota T, Matsumoto J, Shibata T, Murakami KI. Synovial fluid cytokines and proteinases as markers of temporomandibular joint disease. J Oral Maxillofac Surg. 1998;56:192–198. doi: 10.1016/s0278-2391(98)90868-0. [DOI] [PubMed] [Google Scholar]
- 15.Zhang S, Liu X, Yang X, Yang C, Chen M, Haddad MS, Chen Z. Temporomandibular joint disc repositioning using bone anchors: an immediate post surgical evaluation by magnetic resonance imaging. BMC Musculoskelet Disord. 2010;11:262–268. doi: 10.1186/1471-2474-11-262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.He D, Yang C, Chen M, Yang X, Li L, Jiang Q. Surgical treatment of traumatic temporomandibular joint ankylosis with medially displaced residual condyle: surgical methods and long-term results. J Oral Maxillofac Surg. 2011;69:2412–2418. doi: 10.1016/j.joms.2011.04.001. [DOI] [PubMed] [Google Scholar]
- 17.Jiang B, Chen M, Zhang S, Yang C. Disc replacement with temporalis myofascial flap pedicled on the middle temporal artery and vein. China J Oral and Maxillofac Surg. 2009;6:491–494. [Google Scholar]
- 18.Kim YK, Kim SG, Kim BS, Lee JY, Yun PY, Bae JH, et al. Analysis of the cytokine profiles of the synovial fluid in a normal temporomandibular joint: preliminary study. J Craniomaxillofac Surg. 2012 Mar 15; doi: 10.1016/j.jcms.2012.02.002. (Epub ahead of print) [DOI] [PubMed] [Google Scholar]
- 19.Blewis ME, Nugent-Derfus GE, Schmidt TA, Schumacher BL, Sah RL. A model of synovial fluid lubricant composition in normal and injured joints. Eur Cell Mater. 2007;13:26–39. doi: 10.22203/ecm.v013a03. [DOI] [PubMed] [Google Scholar]
- 20.Briston L, Dudhia J, Lees P. Age-related differences in prostaglandin E2 synthesis by equine cartilage explants and synoviocytes. J Vet Pharmacol Ther. 2010;33:268–276. doi: 10.1111/j.1365-2885.2009.01131.x. [DOI] [PubMed] [Google Scholar]
- 21.Roman-Blas JA, Contreras-Blasco MA, Largo R, Alvarez-Soria MA, Castañeda S, Herrero-Beaumont G. Differential effects of the antioxidant n-acetylcysteine on the production of catabolic mediators in IL-1beta-stimulated human osteoarthritic synoviocytes and chondrocytes. Eur J Pharmacol. 2009;623:125–131. doi: 10.1016/j.ejphar.2009.09.016. [DOI] [PubMed] [Google Scholar]
- 22.Lee MC, Goomer RS, Takahashi K, Harwood FL, Amiel M, Amiel D. Transforming growth factor beta one (TGF-beta 1) enhancement of the chondrocytic phenotype in aged perichondrial cells: an in vitro study. Iowa Orthop J. 2000;20:11–16. [PMC free article] [PubMed] [Google Scholar]
- 23.Grimaud E, Heymann D, Rédini F. Recent advances in TGF-beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF-beta in cartilage disorders. Cytokine Growth Factor Rev. 2002;13:241–257. doi: 10.1016/s1359-6101(02)00004-7. [DOI] [PubMed] [Google Scholar]
- 24.Ulrich-Vinther M, Stengaard C, Schwarz EM, Goldring MB, Soballe K. Adeno-associated vector mediated gene transfer of transforming growth factor-beta1 to normal and osteoarthritic human chondrocytes stimulates cartilage anabolism. Eur Cell Mater. 2005;10:40–50. doi: 10.22203/ecm.v010a05. [DOI] [PubMed] [Google Scholar]
- 25.Song JJ, Aswad R, Kanaan RA, Rico MC, Owen TA, Barbe MF, et al. Connective tissue growth factor (CTGF) acts as a downstream mediator of TGF-beta1 to induce mesenchymal cell condensation. J Cell Physiol. 2007;210:398–410. doi: 10.1002/jcp.20850. [DOI] [PubMed] [Google Scholar]
- 26.van der Kraan PM, Blaney Davidson EN, Blom A, van den Berg WB. TGF-beta signaling in chondrocyte terminal differentiation and osteoarthritis: modulation and integration of signaling pathways through receptor-Smads. Osteoarthritis Cartilage. 2009;17:1539–1545. doi: 10.1016/j.joca.2009.06.008. [DOI] [PubMed] [Google Scholar]
- 27.Serra R, Johnson M, Filvaroff EH, LaBorde J, Sheehan DM, Derynck R, Moses HL. Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol. 1997;139:541–552. doi: 10.1083/jcb.139.2.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Pombo-Suarez M, Castaño-Oreja MT, Calaza M, Gomez-Reino J, Gonzalez A. Differential upregulation of the three transforming growth factor beta isoforms in human osteoarthritic cartilage. Ann Rheum Dis. 2009;68:568–571. doi: 10.1136/ard.2008.090217. [DOI] [PubMed] [Google Scholar]
- 29.Niikura T, Reddi AH. Differential regulation of lubricin/superficial zone protein by transforming growth factor beta/bone morphogenetic protein superfamily members in articular chondrocytes and synoviocytes. Arthritis Rheum. 2007;56:2312–2321. doi: 10.1002/art.22659. [DOI] [PubMed] [Google Scholar]
- 30.Boumediene K, Vivien D, Macro M, Bogdanowicz P, Lebrun E, Pujol JP. Modulation of rabbit articular chondrocyte (RAC) proliferation by TGF-beta isoforms. Cell Prolif. 1995;28:221–234. doi: 10.1111/j.1365-2184.1995.tb00065.x. [DOI] [PubMed] [Google Scholar]
- 31.Blaney Davidson EN, van der Kraan PM, van den Berg WB. TGF-beta and osteoarthritis. Osteoarthritis Cartilage. 2007;15:597–604. doi: 10.1016/j.joca.2007.02.005. [DOI] [PubMed] [Google Scholar]
- 32.Takahashi N, Rieneck K, van der Kraan PM, van Beuningen HM, Vitters EL, Bendtzen K, van den Berg WB. Elucidation of IL-1/TGF-beta interactions in mouse chondrocyte cell line by genome-wide gene expression. Osteoarthritis Cartilage. 2005;13:426–438. doi: 10.1016/j.joca.2004.12.010. [DOI] [PubMed] [Google Scholar]
- 33.Liacini A, Sylvester J, Li WQ, Zafarullah M. Mithramycin downregulates proinflammatory cytokine-induced matrix metal-loproteinase gene expression in articular chondrocytes. Arthritis Res Ther. 2005;7:R777–R783. doi: 10.1186/ar1735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Vernal R, Velásquez E, Gamonal J, Garcia-Sanz JA, Silva A, Sanz M. Expression of proinflammatory cytokines in osteoarthritis of the temporomandibular joint. Arch Oral Biol. 2008;53:910–915. doi: 10.1016/j.archoralbio.2008.04.004. [DOI] [PubMed] [Google Scholar]
- 35.Kacena MA, Merrel GA, Konda SR, Wilson KM, Xi Y, Horowitz MC. Inflammation and bony changes at the temporomandibular joint. Cells Tissues Organs. 2001;169:257–264. doi: 10.1159/000047889. [DOI] [PubMed] [Google Scholar]