ANESTHESIA/FACIAL PAIN
Inflammation Is More Distinct in Temporomandibular Joint Osteoarthritis Compared to the Knee Joint Lukas M. Vos, DMD,* Roel Kuijer, PhD,y James J. R. Huddleston Slater, DMD, PhD,z Sjoerd K. Bulstra, MD, PhD,x and Boudewijn Stegenga, DMD, PhDk Purpose:
Most of the current understanding of articular cartilage maintenance and degradation is derived from large load-bearing synovial joints, in particular the knee joint. The aim of this study was to identify valuable degradation markers for cartilage degradation in the temporomandibular joint (TMJ) by comparing the relative concentrations of carboxyterminal telopeptides of collagen types I and II (CTX-I and CTX-II), cartilage oligomeric matrix protein (COMP), and prostaglandin E2 (PGE2) in synovial fluid (SF) of TMJ and knee joints with cartilage degradation.
Materials and Methods:
In this cross-sectional comparative study, participants were recruited from the University Medical Center Groningen, The Netherlands. Patients with TMJ osteoarthritis were compared with patients with knee osteoarthritis. The outcome variables were the relative SF concentrations of CTX-I, CTX-II, COMP, and PGE2. An independent samples Mann-Whitney U test was used to compare the relative concentrations.
Results:
Thirty consecutive patients (9 male, 21 female; mean age, 40.1 yr; standard deviation, 15.3 yr) with TMJ osteoarthritis and 31 consecutive patients (20 male, 11 female; mean age, 37.4 yr; standard deviation, 13.7 yr) who were scheduled for arthroscopy of the knee joint participated in this study. Significant differences were found between relative concentrations of COMP (P = .000) and PGE2 (P = .005), and no significant differences were found between relative concentrations of CTX-I (P = .720) and CTX-II (P = .242).
Conclusions:
Relative SF concentrations of COMP and PGE2 showed significant differences between the TMJ and the knee joint, suggesting that there are differences in pathophysiology and that the inflammatory component may be more distinct in the TMJ. Ó 2013 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg -:1-6, 2013
Most of the current understanding of articular cartilage maintenance and degradation is derived from large load-bearing synovial joints, in particular the knee joint.1 Like the knee joint, the temporomandibular joint (TMJ) is a complex synovial joint with an intraarticular disc and comparable mechanical features. Furthermore, the cartilage degenerative processes are believed to develop similarly.2,3 An important difference between these joints is the type of cartilage that forms the articular lining. In the
knee joint, articular surfaces are covered with hyaline cartilage, whereas in the TMJ, this lining consists of fibrocartilage. In these 2 joints, the cartilage lining consists mainly of collagen. In the TMJ, the fibrocartilage lining contains predominantly collagen type I, whereas hyaline cartilage in the knee joint consists mainly of collagen type II. The serum level of cross-linked carboxyterminal telopeptides of collagen type II (CTX-II) is believed to be a valid marker for the destruction of hyaline
Received from the University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Address correspondence and reprint requests to Dr Vos: Hanzeplein 1, PO Box 30 001, 9700 RB Groningen, The Netherlands;
*Research Assistant, Department of Oral and Maxillofacial Surgery.
e-mail: [email protected]
ySenior Researcher, Department of Biomaterials.
Received June 19 2013
zSenior Researcher, Department of Oral and Maxillofacial Surgery.
Accepted August 16 2013
xProfessor, Department of Orthopedics.
Ó 2013 American Association of Oral and Maxillofacial Surgeons
kProfessor, Department of Oral and Maxillofacial Surgery.
0278-2391/13/01110-5$36.00/0 http://dx.doi.org/10.1016/j.joms.2013.08.022
1
2 cartilage,4-6 although, with regard to synovial fluid (SF) CTX-II, the importance of this marker is ambiguous.6,7 However, because the lining of the articular surfaces of the TMJ is fibrocartilage, this marker may be less accurate for cartilage destruction within the TMJ. Cross-linked carboxyterminal telopeptides of collagen type I (CTX-I) is a degradation product of collagen type I. Therefore, degradation of the fibrocartilage lining within the TMJ is likely to result in higher concentrations of CTX-I in the SF. In contrast, in synovial joints with hyaline cartilage, CTX-I is considered an important marker for bone degeneration.8 Taken together, in the TMJ, CTX-I may be an accurate marker for fibrocartilage degeneration and bone destruction. Serum cartilage oligomeric matrix protein (COMP) is considered a biomarker of cartilage degradation of hyaline and fibrocartilage and a potential prognostic indicator of cartilage damage.9-11 Moreover, COMP is found in the SF of affected joints. In small joints, such as the TMJ, SF COMP may be more accurate as a prognostic indicator than serum COMP. During synovial inflammation, prostaglandin E2 (PGE2), which is the best known lipid mediator that contributes to inflammatory pain,12 is released by synoviocytes.13 It is thought useful for estimating arthritic intensity,14 although in small studies this was not always confirmed.15 Isolation of SF from the TMJ is cumbersome and requires the injection of a physiologic buffer, which should be mixed with SF and then retracted. This procedure results in dilution of the SF sample and an inaccurate determination of marker concentrations and therefore noncomparability with undiluted knee joint samples. To overcome this problem, assessed concentrations of CTX-I, CTX-II, COMP, and PGE2 were added and the sum was set at 100%. Thus, calculated relative concentrations were independent of the dilution factor. Then the relative contribution of each marker was determined within the SF samples obtained from TMJs and from knee joints. Owing to the different types of articular cartilage, it can be hypothesized that clinically relevant differences occur and might be detectable in the SF. The relative SF concentrations of CTX-I, CTX-II, COMP, and PGE2 in TMJs compared with knee joints have not been determined previously. Insight into the differences and similarities between these 2 joints might be helpful in determining the extent to which research outcomes obtained from one joint type can be applied to other joints. The purpose of this study was to identify valuable degradation markers for cartilage degradation in the TMJ and gain insight into the differences and similarities between the TMJ and the knee joint. The investigators hypothesized that the contribution of COMP and PGE2 would be comparable in the 2 joints, that CTX-
OSTEOARTHRITIC JOINT INFLAMMATION
I would be increased and CTX-II would be decreased in the TMJ, and that the opposite would occur in the knee joint. The specific aim of this study was to compare the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in the SF of patients with TMJ osteoarthritis (OA) with those of patients with knee joint OA.
Materials and Methods STUDY DESIGN
This cross-sectional comparative study was conducted at the University Medical Center Groningen (UMCG; Groningen, The Netherlands) from June 2011 through June 2012. Patients with TMJ arthralgia were recruited from the Department of Oral and Maxillofacial Surgery, and patients with knee joint arthralgia were recruited from the Department of Orthopedic Surgery. Before patient recruitment, the research protocol was approved by the ethical committee of the UMCG (METc 2010.131). All participants were informed according to the guidelines of the ethical committee and provided signed informed consent. No studies of sufficient quality were found that compared SF concentrations of markers in the TMJ with markers in the knee. Based on findings of other markers in the TMJ16 and the assumed small differences between the TMJ and the knee joint, an effect size of 0.5 was considered clinically relevant. To detect an effect size of 0.5, with an a value equal to 0.05 and a power of 0.9, 2 groups of 30 patients were needed. To be included in the study, patients had to be at least 18 years of age. In the TMJ group, patients had to be diagnosed with OA according to the revised Research Diagnostic Criteria for Temporomandibular Dysfunction (RDC/TMD17: pain on palpation and during mouth opening and lateral excursions, with crepitation during mandibular movement). In addition, for each patient, an orthopantomogram, a transpharyngeal recording according to Parma, and a transcranial radiograph according to Sch€ uller were obtained. In the knee joint group, patients had to have significant pain and functional impairment of the affected joint, which was supported by visual cartilage destruction at computed tomographic (CT) imaging or magnetic resonance imaging (MRI). Patients were excluded as study subjects if 1) they already used nonsteroidal anti-inflammatory drugs (NSAIDs; including cyclooxygenase-2 inhibitors) or corticosteroids, because of their possible interference with one of the markers under study; 2) they had systemic diseases, such as rheumatoid arthritis; 3) they had a history of surgical intervention of the respective joint; or 4) were pregnant. Before inclusion, patients with TMJ OA received NSAID treatment (ibuprofen 600 mg 3times daily) for 2 weeks. If joint pain was still present, then the
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VOS ET AL
inclusion and exclusion criteria were applied. All included patients were scheduled for arthrocentesis or arthroscopy, and no additional treatment was applied. NSAID treatment was stopped at least 4 weeks before arthrocentesis or arthroscopy was performed to minimize the effect of NSAIDs on PGE2 concentrations. VARIABLES
The predictor variable was the joint type, namely the TMJ or knee joint. The primary outcome variables were the relative concentrations of CTX-I, CTX-II, COMP, and PGE2, which were measured using commercially available enzyme-linked immunosorbent assays for CTX-I and CTX-II (Cusabio Biotech Co, Ltd, Wuhan, China) and for COMP and PGE2 (Abnova, Taipei City, Taiwan). These assays were performed in duplicate according to the manufacturers’ instructions. Demographic variables included age and gender. DATA COLLECTION
In all patients, only the affected joint was sampled. In consequence, 30 SF samples of the TMJ and 31 of the knee joint were collected. Three different operators collected the samples before the arthrocentesis or arthroscopy procedure. SF was collected from the TMJ using intra-articular puncture of the superior joint compartment, which is part of the standard procedure before TMJ arthrocentesis or arthroscopy. To that end, after the injection of approximately 0.2 mL of intra-articular anesthesia (Ultracain D-s forte, SanofiAventis, Paris, France) into the joint, the joint cavity was filled with 2 mL of isotonic sodium chloride solution and homogeneously mixed with the SF using a syringe with pumping motion. Thereafter, 2 mL of the mixture was aspirated and the syringe was removed from the joint. Patients undergoing arthrocentesis or arthroscopy of the knee joint received general or spinal anesthesia. Before intervention and independent of the final surgical procedure, SF was obtained by intra-articular puncture using dry arthroscopy to locate SF accumulations. Only when needed for aspiration was SF minimally diluted with isotonic sodium chloride solution. After fluid collection, elimination of erythrocytes and large proteins was established by immediate centrifugation (25,200g, 10 minutes, 4 C). Thereafter, the samples were stored at 80 C. All samples were analyzed simultaneously. STATISTICAL ANALYSIS
Relative SF concentrations of each marker were calculated by normalization (sum of the 4 markers within an SF sample, 100%). The dilution factor plays no role because the relative concentrations of the markers within a sample remain the same: with dilution, all markers within a sample change equally. The distribu-
tion of the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in TMJ SF was compared with the distribution of the relative concentrations of these markers in knee joints using an independent samples Mann-Whitney U test (SPSS 18.0, SPSS, Inc, Chicago, IL).
Results Thirty consecutive patients who were scheduled for arthrocentesis or arthroscopy of the TMJ and 31 consecutive patients who were scheduled for arthrocentesis or arthroscopy of the knee joint met the inclusion criteria and participated in this study (Table 1). There was a significant difference with regard to gender between the 2 groups (P = .007). However, age and gender did not influence the relative concentrations significantly (P > .01; Table 2). Concentrations of CTX-I, CTX-II, COMP, and PGE2 were measured regardless of the dilution of the samples. An example of the distribution of the relative concentrations is provided in Figure 1. Detectable concentrations of CTX-I were found in 4 of the 30 TMJ samples and in 6 of the 31 knee joint samples. CTX-II, COMP, and PGE2 were detectable in all samples. The relative concentration of each marker was determined for each sample. After normalization, median relative concentration and interquartile range were used to compare the 2 groups. Significant differences were found between relative concentrations of COMP (P = .000) and PGE2 (P = .005), and no significant differences were found between relative concentrations of CTX-I (P = .720) and CTX-II (P = .242; Table 3).
Discussion The purpose of this study was to identify valuable degradation markers for cartilage degradation in the TMJ and gain insight into the differences and similarities between the TMJ and the knee joint. The investigators hypothesized that the contribution of COMP and PGE2 would be comparable in the 2 joints, that CTXI would be increased and CTX-II would be decreased in the TMJ, and that the opposite would occur in the
Table 1. PATIENTS’ CHARACTERISTICS
Characteristics Sample size, n Women, n (%) Age (yr), mean (SD)
TMJ
Knee Joint
P Value
30 21 (70) 40.1 (15.3)
31 11 (34) 37.4 (13.7)
.007 .457
Abbreviations: SD, standard deviation; TMJ, temporomandibular joint. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
4
OSTEOARTHRITIC JOINT INFLAMMATION
Table 2. CORRELATIONS OF PATIENTS’ CHARACTERISTICS AND RELATIVE CONCENTRATIONS OF CTX-I, CTX-II, COMP, AND PGE2
Characteristics Sample size, n Gender, P value* Age, Spearmen r (P value)
CTX-I
CTX-II
COMP
PGE2
61 1.000 0.211 (.103)
61 0.603 0.096 (.460)
61 0.076 0.045 (.733)
61 0.279 0.188 (.146)
Abbreviations: COMP, cartilage oligomeric matrix protein; CTX-I, carboxyterminal telopeptides of collagen type I; CTX-II, carboxyterminal telopeptides of collagen type II; PGE2, prostaglandin E2. * Independent samples Mann-Whitney U test. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
knee joint. The specific aim of this study was to compare the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in the SF of patients with TMJ OA with those of patients with knee joint OA. The results of this study showed significant differences in the relative concentrations of COMP and PGE2 between the TMJ and the knee joint, suggesting differences in pathophysiology between the 2 joints. Based on the composition of fibrocartilage and hyaline cartilage, a significant difference was expected between the 2 joints with regard to the contribution of CTX-I and CTX-II. However, according to the results of this study, CTX-II seemed to be the most prominent cartilage degradation product in the 2 joints, whereas CTX-I was not detectable in most samples. In this study, relative SF concentrations were determined, in contrast to most other studies in which only absolute concentrations were measured.18,19 Similar concentrations would suggest a similar pathophysiology2,3,20,21; however, the results of this study suggested differences in pathophysiology between the TMJ and the knee joint because the relative quantities of some of these markers appeared to differ significantly. In particular, the contributions of COMP and PGE2 differed between the 2 joints,
suggesting that the inflammatory component in the pathophysiology of cartilage destruction might be more distinct in the TMJ. The hypothesis that there are indeed pathophysiologic differences in cartilage destruction between the TMJ and the knee joint is supported by the findings of Kapila et al22 who investigated the effect of relaxin-induced matrix metalloproteinases on the cartilage matrix. CTX-I was detected in only 4 of the 30 TMJ samples obtained from diseased joints. CTX-I was assumed to be a detectable SF marker for fibrocartilage degradation, because fibrocartilage consists mainly of collagen type I, of which CTX-I is a degradation product. However, the detectable concentrations of CTX-I in these 4 cases might have been due to the degradation of underlying bone rather than fibrocartilage, because CTX-I is considered an important marker for bone degeneration.8 With regard to CTX-II, the unexpected high relative concentrations in the TMJ might indicate that the superficial layer of the articular fibrocartilage contains more collagen type II than the inner part. This is supported by Kondoh et al23 who found a significantly higher collagen type II synthesis in the articular surfaces than in the inner part of the TMJ disc.
FIGURE 1. Distribution of relative synovial fluid concentrations of CTX-I, CTX-II, COMP, and PGE2 in 2 patients. Relative concentrations of each marker were calculated by normalization (sum of the 4 markers within the sample were set at 100%). COMP, cartilage oligomeric matrix protein; CTX-I, carboxyterminal telopeptides of collagen type I; CTX-II, carboxyterminal telopeptides of collagen type II; PGE2, prostaglandin E2; TMJ, temporomandibular joint. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
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VOS ET AL
Table 3. RELATIVE CONCENTRATIONS OF CTX-I, CTX-II, COMP, AND PGE2
Joint Type Relative concentrations in TMJ, % (IQR) Relative concentrations in knee joint, % (IQR) P value
CTX-I
CTX-II
COMP
PGE2
0.00 (0.00) 0.00 (0.00) .720
74.29 (62.06) 82.92 (26.54) .242
0.76 (3.37) 6.62 (7.65) .000
13.19 (32.20) 2.82 (9.68) .005
Abbreviations: COMP, cartilage oligomeric matrix protein; CTX-I, carboxyterminal telopeptides of collagen type I; CTX-II, carboxyterminal telopeptides of collagen type II; IQR, interquartile range; PGE2, prostaglandin E2. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
To obtain SF from the TMJ, it is inevitable that the fluid in the joint cavity will be diluted. In some cases, this also applies to the knee joint. In this study, isotonic sodium chloride solution was used as a physiologic buffer. Dilution of the SF may have been responsible in particular for the undetectability of CTX-I in most TMJ samples. However, because hyaline cartilage in the knee joint consists predominantly of type II collagen, high relative concentrations of CTX-I were expected mainly owing to bone or meniscus involvement. An assessment of relative concentrations allows for SF analysis independent of the sample dilution and might be more suitable for routine clinical use. Furthermore, this method facilitates comparison with other joints because of its independence of the dilution factor. However, this method is not commonly used in research; therefore, a comparison of the results of this study with the available literature is indirect. The relative concentrations indicate the contribution of the markers, but do not determine the absolute increase or decrease as in most other studies. Because cartilage degeneration in the TMJ is often difficult to detect with noninvasive techniques, the samples were obtained from patients with obvious joint pain, impaired mandibular movement, and crepitus (OA according to the RDC/TMD IIIb17,24) that did not improve after 2 weeks of NSAID treatment (exclusion, acute arthritis). Subsequently, the diagnosis was confirmed by the radiographic recordings. Knee joint samples were obtained from patients with significant pain, functional impairment, and cartilage destruction visible at CT scan or MRI. However, notwithstanding accurate patient selection, heterogeneity might have been introduced in the 2 groups owing to individual fluctuations in the course of the disease after inclusion and before sample selection. There was no normal distribution of the relative concentrations. Interpatient variation and fluctuations over time within patients and possible differences in disease classification, as mentioned earlier, might have contributed to the large variation. With regard to this variation, the sample of recruited patients may have been too small to reflect an assumed normal distribution.
Relative SF concentrations of COMP and PGE2 showed significant differences between the TMJ and the knee joint, suggesting that there are differences in pathophysiology and that the inflammatory component might be more distinct in the TMJ.
References 1. Yokota H, Leong DJ, Sun HB: Mechanical loading: Bone remodeling and cartilage maintenance. Curr Osteoporos Rep 9:237, 2011 2. Holmlund A, Ekblom A, Hansson P, et al: Concentrations of neuropeptides substance P, neurokinin A, calcitonin gene-related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid of the human temporomandibular joint. A correlation with symptoms, signs and arthroscopic findings. Int J Oral Maxillofac Surg 20:228, 1991 3. Quinn JH, Bazan NG: Identification of prostaglandin E2 and leukotriene B4 in the synovial fluid of painful, dysfunctional temporomandibular joints. J Oral Maxillofac Surg 48:968, 1990 4. Lohmander LS, Atley LM, Pietka TA, et al: The release of crosslinked peptides from type II collagen into human synovial fluid is increased soon after joint injury and in osteoarthritis. Arthritis Rheum 48:3130, 2003 5. Duclos ME, Roualdes O, Cararo R, et al: Significance of the serum CTX-II level in an osteoarthritis animal model: A 5-month longitudinal study. Osteoarthr Cartil 18:1467, 2010 6. Oestergaard S, Chouinard L, Doyle N, et al: The utility of measuring C-terminal telopeptides of collagen type II (CTX-II) in serum and synovial fluid samples for estimation of articular cartilage status in experimental models of destructive joint diseases. Osteoarthritis Cartilage 14:670, 2006 7. Catterall JB, Stabler TV, Flannery CR, et al: Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254). Arthritis Res Ther 12:R229, 2010 8. Berry PA, Maciewicz RA, Cicuttini FM, et al: Markers of bone formation and resorption identify subgroups of patients with clinical knee osteoarthritis who have reduced rates of cartilage loss. J Rheumatol 37:1252, 2010 9. Sowers M, Karvonen-Gutierrez CA, Palmieri-Smith R, et al: Knee osteoarthritis in obese women with cardiometabolic clustering. Arthritis Rheum 61:1328, 2009 10. Tseng S, Reddi AH, Di Cesare PE: Cartilage oligomeric matrix protein (COMP): A biomarker of arthritis. Biomark Insights 4:33, 2009 11. Kraus VB, Kepler TB, Stabler T, et al: First qualification study of serum biomarkers as indicators of total body burden of osteoarthritis. PLoS One 5:e9739, 2010 12. Kawabata A: Prostaglandin E2 and pain—An update. Biol Pharm Bull 34:1170, 2011 13. Li X, Ellman M, Muddasani P, et al: Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis. Arthritis Rheum 60:513, 2009 14. Amin AR, Attur M, Patel RN, et al: Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest 99:1231, 1997
6 15. Murakami KI, Shibata T, Kubota E, et al: Intra-articular levels of prostaglandin E2, hyaluronic acid, and chondroitin-4 and -6 sulfates in the temporomandibular joint synovial fluid of patients with internal derangement. J Oral Maxillofac Surg 56: 199, 1998 16. Kacena MA, Merrel GA, Konda SR, et al: Inflammation and bony changes at the temporomandibular joint. Cells Tissues Organs 169:257, 2001 17. Dworkin SF, LeResche L: Research diagnostic criteria for temporomandibular disorders: Review, criteria, examinations and specifications, critique. J Craniomandib Disord 6:301, 1992 18. Morozzi G, Fabbroni M, Bellisai F, et al: Cartilage oligomeric matrix protein level in rheumatic diseases: Potential use as a marker for measuring articular cartilage damage and/or the therapeutic efficacy of treatments. Ann N Y Acad Sci 1108:398, 2007 19. Kraus VB: Osteoarthritis year 2010 in review: Biochemical markers. Osteoarthritis Cartilage 19:346, 2011
OSTEOARTHRITIC JOINT INFLAMMATION 20. Polur I, Lee PL, Servais JM, et al: Role of HTRA1, a serine protease, in the progression of articular cartilage degeneration. Histol Histopathol 25:599, 2010 21. Tominaga K, Alstergren P, Kurita H, et al: Interleukin-1beta in antigen-induced arthritis of the rabbit temporomandibular joint. Arch Oral Biol 46:539, 2001 22. Kapila S, Wang W, Uston K: Matrix metalloproteinase induction by relaxin causes cartilage matrix degradation in target synovial joints. Ann N Y Acad Sci 1160:322, 2009 23. Kondoh T, Hamada Y, Iino M, et al: Regional differences of type II collagen synthesis in the human temporomandibular joint disc: Immunolocalization study of carboxy-terminal type II procollagen peptide (chondrocalcin). Arch Oral Biol 48:621, 2003 24. Schiffman EL, Truelove EL, Ohrbach R, et al: The Research Diagnostic Criteria for Temporomandibular Disorders. I: Overview and methodology for assessment of validity. J Orofac Pain 24:7, 2010
Inflammation Is More Distinct in Temporomandibular Joint Osteoarthritis Compared to the Knee Joint Lukas M. Vos, DMD,* Roel Kuijer, PhD,y James J. R. Huddleston Slater, DMD, PhD,z Sjoerd K. Bulstra, MD, PhD,x and Boudewijn Stegenga, DMD, PhDk Purpose:
Most of the current understanding of articular cartilage maintenance and degradation is derived from large load-bearing synovial joints, in particular the knee joint. The aim of this study was to identify valuable degradation markers for cartilage degradation in the temporomandibular joint (TMJ) by comparing the relative concentrations of carboxyterminal telopeptides of collagen types I and II (CTX-I and CTX-II), cartilage oligomeric matrix protein (COMP), and prostaglandin E2 (PGE2) in synovial fluid (SF) of TMJ and knee joints with cartilage degradation.
Materials and Methods:
In this cross-sectional comparative study, participants were recruited from the University Medical Center Groningen, The Netherlands. Patients with TMJ osteoarthritis were compared with patients with knee osteoarthritis. The outcome variables were the relative SF concentrations of CTX-I, CTX-II, COMP, and PGE2. An independent samples Mann-Whitney U test was used to compare the relative concentrations.
Results:
Thirty consecutive patients (9 male, 21 female; mean age, 40.1 yr; standard deviation, 15.3 yr) with TMJ osteoarthritis and 31 consecutive patients (20 male, 11 female; mean age, 37.4 yr; standard deviation, 13.7 yr) who were scheduled for arthroscopy of the knee joint participated in this study. Significant differences were found between relative concentrations of COMP (P = .000) and PGE2 (P = .005), and no significant differences were found between relative concentrations of CTX-I (P = .720) and CTX-II (P = .242).
Conclusions:
Relative SF concentrations of COMP and PGE2 showed significant differences between the TMJ and the knee joint, suggesting that there are differences in pathophysiology and that the inflammatory component may be more distinct in the TMJ. Ó 2013 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg -:1-6, 2013
Most of the current understanding of articular cartilage maintenance and degradation is derived from large load-bearing synovial joints, in particular the knee joint.1 Like the knee joint, the temporomandibular joint (TMJ) is a complex synovial joint with an intraarticular disc and comparable mechanical features. Furthermore, the cartilage degenerative processes are believed to develop similarly.2,3 An important difference between these joints is the type of cartilage that forms the articular lining. In the
knee joint, articular surfaces are covered with hyaline cartilage, whereas in the TMJ, this lining consists of fibrocartilage. In these 2 joints, the cartilage lining consists mainly of collagen. In the TMJ, the fibrocartilage lining contains predominantly collagen type I, whereas hyaline cartilage in the knee joint consists mainly of collagen type II. The serum level of cross-linked carboxyterminal telopeptides of collagen type II (CTX-II) is believed to be a valid marker for the destruction of hyaline
Received from the University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Address correspondence and reprint requests to Dr Vos: Hanzeplein 1, PO Box 30 001, 9700 RB Groningen, The Netherlands;
*Research Assistant, Department of Oral and Maxillofacial Surgery.
e-mail: [email protected]
ySenior Researcher, Department of Biomaterials.
Received June 19 2013
zSenior Researcher, Department of Oral and Maxillofacial Surgery.
Accepted August 16 2013
xProfessor, Department of Orthopedics.
Ó 2013 American Association of Oral and Maxillofacial Surgeons
kProfessor, Department of Oral and Maxillofacial Surgery.
0278-2391/13/01110-5$36.00/0 http://dx.doi.org/10.1016/j.joms.2013.08.022
1
2 cartilage,4-6 although, with regard to synovial fluid (SF) CTX-II, the importance of this marker is ambiguous.6,7 However, because the lining of the articular surfaces of the TMJ is fibrocartilage, this marker may be less accurate for cartilage destruction within the TMJ. Cross-linked carboxyterminal telopeptides of collagen type I (CTX-I) is a degradation product of collagen type I. Therefore, degradation of the fibrocartilage lining within the TMJ is likely to result in higher concentrations of CTX-I in the SF. In contrast, in synovial joints with hyaline cartilage, CTX-I is considered an important marker for bone degeneration.8 Taken together, in the TMJ, CTX-I may be an accurate marker for fibrocartilage degeneration and bone destruction. Serum cartilage oligomeric matrix protein (COMP) is considered a biomarker of cartilage degradation of hyaline and fibrocartilage and a potential prognostic indicator of cartilage damage.9-11 Moreover, COMP is found in the SF of affected joints. In small joints, such as the TMJ, SF COMP may be more accurate as a prognostic indicator than serum COMP. During synovial inflammation, prostaglandin E2 (PGE2), which is the best known lipid mediator that contributes to inflammatory pain,12 is released by synoviocytes.13 It is thought useful for estimating arthritic intensity,14 although in small studies this was not always confirmed.15 Isolation of SF from the TMJ is cumbersome and requires the injection of a physiologic buffer, which should be mixed with SF and then retracted. This procedure results in dilution of the SF sample and an inaccurate determination of marker concentrations and therefore noncomparability with undiluted knee joint samples. To overcome this problem, assessed concentrations of CTX-I, CTX-II, COMP, and PGE2 were added and the sum was set at 100%. Thus, calculated relative concentrations were independent of the dilution factor. Then the relative contribution of each marker was determined within the SF samples obtained from TMJs and from knee joints. Owing to the different types of articular cartilage, it can be hypothesized that clinically relevant differences occur and might be detectable in the SF. The relative SF concentrations of CTX-I, CTX-II, COMP, and PGE2 in TMJs compared with knee joints have not been determined previously. Insight into the differences and similarities between these 2 joints might be helpful in determining the extent to which research outcomes obtained from one joint type can be applied to other joints. The purpose of this study was to identify valuable degradation markers for cartilage degradation in the TMJ and gain insight into the differences and similarities between the TMJ and the knee joint. The investigators hypothesized that the contribution of COMP and PGE2 would be comparable in the 2 joints, that CTX-
OSTEOARTHRITIC JOINT INFLAMMATION
I would be increased and CTX-II would be decreased in the TMJ, and that the opposite would occur in the knee joint. The specific aim of this study was to compare the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in the SF of patients with TMJ osteoarthritis (OA) with those of patients with knee joint OA.
Materials and Methods STUDY DESIGN
This cross-sectional comparative study was conducted at the University Medical Center Groningen (UMCG; Groningen, The Netherlands) from June 2011 through June 2012. Patients with TMJ arthralgia were recruited from the Department of Oral and Maxillofacial Surgery, and patients with knee joint arthralgia were recruited from the Department of Orthopedic Surgery. Before patient recruitment, the research protocol was approved by the ethical committee of the UMCG (METc 2010.131). All participants were informed according to the guidelines of the ethical committee and provided signed informed consent. No studies of sufficient quality were found that compared SF concentrations of markers in the TMJ with markers in the knee. Based on findings of other markers in the TMJ16 and the assumed small differences between the TMJ and the knee joint, an effect size of 0.5 was considered clinically relevant. To detect an effect size of 0.5, with an a value equal to 0.05 and a power of 0.9, 2 groups of 30 patients were needed. To be included in the study, patients had to be at least 18 years of age. In the TMJ group, patients had to be diagnosed with OA according to the revised Research Diagnostic Criteria for Temporomandibular Dysfunction (RDC/TMD17: pain on palpation and during mouth opening and lateral excursions, with crepitation during mandibular movement). In addition, for each patient, an orthopantomogram, a transpharyngeal recording according to Parma, and a transcranial radiograph according to Sch€ uller were obtained. In the knee joint group, patients had to have significant pain and functional impairment of the affected joint, which was supported by visual cartilage destruction at computed tomographic (CT) imaging or magnetic resonance imaging (MRI). Patients were excluded as study subjects if 1) they already used nonsteroidal anti-inflammatory drugs (NSAIDs; including cyclooxygenase-2 inhibitors) or corticosteroids, because of their possible interference with one of the markers under study; 2) they had systemic diseases, such as rheumatoid arthritis; 3) they had a history of surgical intervention of the respective joint; or 4) were pregnant. Before inclusion, patients with TMJ OA received NSAID treatment (ibuprofen 600 mg 3times daily) for 2 weeks. If joint pain was still present, then the
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inclusion and exclusion criteria were applied. All included patients were scheduled for arthrocentesis or arthroscopy, and no additional treatment was applied. NSAID treatment was stopped at least 4 weeks before arthrocentesis or arthroscopy was performed to minimize the effect of NSAIDs on PGE2 concentrations. VARIABLES
The predictor variable was the joint type, namely the TMJ or knee joint. The primary outcome variables were the relative concentrations of CTX-I, CTX-II, COMP, and PGE2, which were measured using commercially available enzyme-linked immunosorbent assays for CTX-I and CTX-II (Cusabio Biotech Co, Ltd, Wuhan, China) and for COMP and PGE2 (Abnova, Taipei City, Taiwan). These assays were performed in duplicate according to the manufacturers’ instructions. Demographic variables included age and gender. DATA COLLECTION
In all patients, only the affected joint was sampled. In consequence, 30 SF samples of the TMJ and 31 of the knee joint were collected. Three different operators collected the samples before the arthrocentesis or arthroscopy procedure. SF was collected from the TMJ using intra-articular puncture of the superior joint compartment, which is part of the standard procedure before TMJ arthrocentesis or arthroscopy. To that end, after the injection of approximately 0.2 mL of intra-articular anesthesia (Ultracain D-s forte, SanofiAventis, Paris, France) into the joint, the joint cavity was filled with 2 mL of isotonic sodium chloride solution and homogeneously mixed with the SF using a syringe with pumping motion. Thereafter, 2 mL of the mixture was aspirated and the syringe was removed from the joint. Patients undergoing arthrocentesis or arthroscopy of the knee joint received general or spinal anesthesia. Before intervention and independent of the final surgical procedure, SF was obtained by intra-articular puncture using dry arthroscopy to locate SF accumulations. Only when needed for aspiration was SF minimally diluted with isotonic sodium chloride solution. After fluid collection, elimination of erythrocytes and large proteins was established by immediate centrifugation (25,200g, 10 minutes, 4 C). Thereafter, the samples were stored at 80 C. All samples were analyzed simultaneously. STATISTICAL ANALYSIS
Relative SF concentrations of each marker were calculated by normalization (sum of the 4 markers within an SF sample, 100%). The dilution factor plays no role because the relative concentrations of the markers within a sample remain the same: with dilution, all markers within a sample change equally. The distribu-
tion of the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in TMJ SF was compared with the distribution of the relative concentrations of these markers in knee joints using an independent samples Mann-Whitney U test (SPSS 18.0, SPSS, Inc, Chicago, IL).
Results Thirty consecutive patients who were scheduled for arthrocentesis or arthroscopy of the TMJ and 31 consecutive patients who were scheduled for arthrocentesis or arthroscopy of the knee joint met the inclusion criteria and participated in this study (Table 1). There was a significant difference with regard to gender between the 2 groups (P = .007). However, age and gender did not influence the relative concentrations significantly (P > .01; Table 2). Concentrations of CTX-I, CTX-II, COMP, and PGE2 were measured regardless of the dilution of the samples. An example of the distribution of the relative concentrations is provided in Figure 1. Detectable concentrations of CTX-I were found in 4 of the 30 TMJ samples and in 6 of the 31 knee joint samples. CTX-II, COMP, and PGE2 were detectable in all samples. The relative concentration of each marker was determined for each sample. After normalization, median relative concentration and interquartile range were used to compare the 2 groups. Significant differences were found between relative concentrations of COMP (P = .000) and PGE2 (P = .005), and no significant differences were found between relative concentrations of CTX-I (P = .720) and CTX-II (P = .242; Table 3).
Discussion The purpose of this study was to identify valuable degradation markers for cartilage degradation in the TMJ and gain insight into the differences and similarities between the TMJ and the knee joint. The investigators hypothesized that the contribution of COMP and PGE2 would be comparable in the 2 joints, that CTXI would be increased and CTX-II would be decreased in the TMJ, and that the opposite would occur in the
Table 1. PATIENTS’ CHARACTERISTICS
Characteristics Sample size, n Women, n (%) Age (yr), mean (SD)
TMJ
Knee Joint
P Value
30 21 (70) 40.1 (15.3)
31 11 (34) 37.4 (13.7)
.007 .457
Abbreviations: SD, standard deviation; TMJ, temporomandibular joint. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
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Table 2. CORRELATIONS OF PATIENTS’ CHARACTERISTICS AND RELATIVE CONCENTRATIONS OF CTX-I, CTX-II, COMP, AND PGE2
Characteristics Sample size, n Gender, P value* Age, Spearmen r (P value)
CTX-I
CTX-II
COMP
PGE2
61 1.000 0.211 (.103)
61 0.603 0.096 (.460)
61 0.076 0.045 (.733)
61 0.279 0.188 (.146)
Abbreviations: COMP, cartilage oligomeric matrix protein; CTX-I, carboxyterminal telopeptides of collagen type I; CTX-II, carboxyterminal telopeptides of collagen type II; PGE2, prostaglandin E2. * Independent samples Mann-Whitney U test. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
knee joint. The specific aim of this study was to compare the relative concentrations of CTX-I, CTX-II, COMP, and PGE2 in the SF of patients with TMJ OA with those of patients with knee joint OA. The results of this study showed significant differences in the relative concentrations of COMP and PGE2 between the TMJ and the knee joint, suggesting differences in pathophysiology between the 2 joints. Based on the composition of fibrocartilage and hyaline cartilage, a significant difference was expected between the 2 joints with regard to the contribution of CTX-I and CTX-II. However, according to the results of this study, CTX-II seemed to be the most prominent cartilage degradation product in the 2 joints, whereas CTX-I was not detectable in most samples. In this study, relative SF concentrations were determined, in contrast to most other studies in which only absolute concentrations were measured.18,19 Similar concentrations would suggest a similar pathophysiology2,3,20,21; however, the results of this study suggested differences in pathophysiology between the TMJ and the knee joint because the relative quantities of some of these markers appeared to differ significantly. In particular, the contributions of COMP and PGE2 differed between the 2 joints,
suggesting that the inflammatory component in the pathophysiology of cartilage destruction might be more distinct in the TMJ. The hypothesis that there are indeed pathophysiologic differences in cartilage destruction between the TMJ and the knee joint is supported by the findings of Kapila et al22 who investigated the effect of relaxin-induced matrix metalloproteinases on the cartilage matrix. CTX-I was detected in only 4 of the 30 TMJ samples obtained from diseased joints. CTX-I was assumed to be a detectable SF marker for fibrocartilage degradation, because fibrocartilage consists mainly of collagen type I, of which CTX-I is a degradation product. However, the detectable concentrations of CTX-I in these 4 cases might have been due to the degradation of underlying bone rather than fibrocartilage, because CTX-I is considered an important marker for bone degeneration.8 With regard to CTX-II, the unexpected high relative concentrations in the TMJ might indicate that the superficial layer of the articular fibrocartilage contains more collagen type II than the inner part. This is supported by Kondoh et al23 who found a significantly higher collagen type II synthesis in the articular surfaces than in the inner part of the TMJ disc.
FIGURE 1. Distribution of relative synovial fluid concentrations of CTX-I, CTX-II, COMP, and PGE2 in 2 patients. Relative concentrations of each marker were calculated by normalization (sum of the 4 markers within the sample were set at 100%). COMP, cartilage oligomeric matrix protein; CTX-I, carboxyterminal telopeptides of collagen type I; CTX-II, carboxyterminal telopeptides of collagen type II; PGE2, prostaglandin E2; TMJ, temporomandibular joint. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
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Table 3. RELATIVE CONCENTRATIONS OF CTX-I, CTX-II, COMP, AND PGE2
Joint Type Relative concentrations in TMJ, % (IQR) Relative concentrations in knee joint, % (IQR) P value
CTX-I
CTX-II
COMP
PGE2
0.00 (0.00) 0.00 (0.00) .720
74.29 (62.06) 82.92 (26.54) .242
0.76 (3.37) 6.62 (7.65) .000
13.19 (32.20) 2.82 (9.68) .005
Abbreviations: COMP, cartilage oligomeric matrix protein; CTX-I, carboxyterminal telopeptides of collagen type I; CTX-II, carboxyterminal telopeptides of collagen type II; IQR, interquartile range; PGE2, prostaglandin E2. Vos et al. Osteoarthritic Joint Inflammation. J Oral Maxillofac Surg 2013.
To obtain SF from the TMJ, it is inevitable that the fluid in the joint cavity will be diluted. In some cases, this also applies to the knee joint. In this study, isotonic sodium chloride solution was used as a physiologic buffer. Dilution of the SF may have been responsible in particular for the undetectability of CTX-I in most TMJ samples. However, because hyaline cartilage in the knee joint consists predominantly of type II collagen, high relative concentrations of CTX-I were expected mainly owing to bone or meniscus involvement. An assessment of relative concentrations allows for SF analysis independent of the sample dilution and might be more suitable for routine clinical use. Furthermore, this method facilitates comparison with other joints because of its independence of the dilution factor. However, this method is not commonly used in research; therefore, a comparison of the results of this study with the available literature is indirect. The relative concentrations indicate the contribution of the markers, but do not determine the absolute increase or decrease as in most other studies. Because cartilage degeneration in the TMJ is often difficult to detect with noninvasive techniques, the samples were obtained from patients with obvious joint pain, impaired mandibular movement, and crepitus (OA according to the RDC/TMD IIIb17,24) that did not improve after 2 weeks of NSAID treatment (exclusion, acute arthritis). Subsequently, the diagnosis was confirmed by the radiographic recordings. Knee joint samples were obtained from patients with significant pain, functional impairment, and cartilage destruction visible at CT scan or MRI. However, notwithstanding accurate patient selection, heterogeneity might have been introduced in the 2 groups owing to individual fluctuations in the course of the disease after inclusion and before sample selection. There was no normal distribution of the relative concentrations. Interpatient variation and fluctuations over time within patients and possible differences in disease classification, as mentioned earlier, might have contributed to the large variation. With regard to this variation, the sample of recruited patients may have been too small to reflect an assumed normal distribution.
Relative SF concentrations of COMP and PGE2 showed significant differences between the TMJ and the knee joint, suggesting that there are differences in pathophysiology and that the inflammatory component might be more distinct in the TMJ.
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6 15. Murakami KI, Shibata T, Kubota E, et al: Intra-articular levels of prostaglandin E2, hyaluronic acid, and chondroitin-4 and -6 sulfates in the temporomandibular joint synovial fluid of patients with internal derangement. J Oral Maxillofac Surg 56: 199, 1998 16. Kacena MA, Merrel GA, Konda SR, et al: Inflammation and bony changes at the temporomandibular joint. Cells Tissues Organs 169:257, 2001 17. Dworkin SF, LeResche L: Research diagnostic criteria for temporomandibular disorders: Review, criteria, examinations and specifications, critique. J Craniomandib Disord 6:301, 1992 18. Morozzi G, Fabbroni M, Bellisai F, et al: Cartilage oligomeric matrix protein level in rheumatic diseases: Potential use as a marker for measuring articular cartilage damage and/or the therapeutic efficacy of treatments. Ann N Y Acad Sci 1108:398, 2007 19. Kraus VB: Osteoarthritis year 2010 in review: Biochemical markers. Osteoarthritis Cartilage 19:346, 2011
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