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CURRENT THERAPY

J Oral Maxillofac Surg67:2497-2504, 2009

Temporomandibular Joint Pain andSynovial Fluid Analysis: A Review

of the LiteratureGary F. Bouloux, MD, DDS, MDSc*

The pathophysiology of temporomandibular joint pain is not well understood. A significant amount ofresearch has been conducted to evaluate synovial fluid in these patients and in healthy controls.Qualitative and quantitative analyses of the synovial fluid have shown a significant difference betweenthese groups. A multitude of inflammatory mediators and degradation products have been identified. Theconcentration of these products has been shown to correlate with several clinical parameters includingpain, chronicity, severity of degenerative change, and response to treatment. A common inflammatorypathway would appear to be involved in most patients. At the present time, synovial fluid analysis doesnot have the sensitivity or specificity to allow specific diagnoses and targeted treatment. Continuedresearch with the specific aim of establishing more appropriate therapeutic modalities based on thebiochemical pathways is warranted.© 2009 American Association of Oral and Maxillofacial Surgeons

J Oral Maxillofac Surg 67:2497-2504, 2009

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emporomandibular joint (TMJ) pain is complicated,nd multiple factors are thought to contribute to theonscious perception of pain. An acute inflammatoryesponse in tissue is known to result in peripheralensitization and impulse transmission along ascend-ng neural pathways that ultimately lead to pain per-eption. Modulation of this inflammatory processhrough the use of nonsteroidal anti-inflammatoryrugs has historically been the mainstay of pain man-gement. However, it is unknown whether all pa-ients with chronic pain have experienced a preced-ng acute inflammatory process. The mechanism by

hich patients develop chronic pain is more compli-ated, involving physiologic and psychological fac-ors. In addition to chronic inflammation, potentialauses of chronic pain include neurotropic agents,entral sensitization, sympathetically mediated pain,nd deafferentation.1

*Assistant Professor, Oral and Maxillofacial Surgery, Emory Uni-

ersity, Atlanta, GA.

Address reprint requests and correspondence to Dr Bouloux:

ral and Maxillofacial Surgery, Emory University, 1365B Clifton

oad NE, Suite 2300, Atlanta, GA 30322; e-mail: gfboulo@emory.

du

2009 American Association of Oral and Maxillofacial Surgeons

278-2391/09/6711-0027$36.00/0

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2497

The initial approach to any patient with facial painequires a complete history and physical examination.his provides the clinician with the ability to developprovisional or differential diagnosis. Potential causesf TMJ pain are numerous, but one of the primaryoals is to identify confounding myogenous sources.yofascial pain is common and can complicate intra-

rticular sources of pain. Knowing whether the myo-ascial pain is primary or secondary to the intra-artic-lar pain is important, but this can be very difficult toscertain. Facial pain that is localized to the TMJ isften attributed to internal derangement, synovitis,apsulitis, fibrous adhesions, or osteoarthritis (OA).hese entities are not mutually exclusive and mayoexist.TMJ pain may represent a gradual progression from

oint inflammation and synovitis to fibrous adhesions,nternal derangement, and OA.2,3 The source of thenitial inflammation may be reactive species, such aseroxide, hydroxyl radical, hydroxide anion, super-xide anion, or ferryl radicals. These reactive speciesay develop in response to direct mechanical trauma,ypoxia/reperfusion injury, or microbleeding.3 Freeadicals may further develop secondary to the pres-nce of inflammatory cytokines and may modulateytokine production. The upregulation of cyclo-oxy-enase-2 has been identified in synovial lining, infil-rating mononuclear cells, fibroblast-like cells, andndothelial cells in the synovium of patients with

nternal derangement and OA.4 This would ultimately

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2498 TMJ PAIN AND SYNOVIAL FLUID ANALYSIS

ead to the increased production of prostaglandinsnd leukotrienes. Inflammation is likely to play a rolen many patients with TMJ pain.

To understand the effect of inflammation on theMJ, a basic understanding of joint histology and

unction is required. The synovial membrane and sy-ovial fluid are thought to play an integral role inormal joint function and inflammation. Structurally,he synovial membrane is composed of 1 to 3 cellayers and an extracellular matrix that rests on a vas-ular subintimal connective tissue base. Three cellypes exist within this synovial intima. Type A cellsre considered phagocytic cells, type B cells are se-retory cells producing hyaluronic acid (HA), proteo-lycans, and lubricating glycoprotein, and type C cellsre thought to be intermediate in their function. Theynovial fluid composition is complex. Lipids, choles-erol, phospholipids, HA, glycosaminoglycans, albu-in, immunoglobulin, elastase, collagenase, cathep-

ins, proteinase inhibitors, phospholipase A2, andlpha-2-macroglobulin have been identified.5,6 How-ver, there is no synovial lining on the articulatingurfaces of the condyle, glenoid fossa, or articularisc. The articulating surfaces and articular disc areomposed of fibrocartilage. Within the fibrocartilage,he extracellular matrix is composed of large aggre-ates of HA and proteoglycan monomers. The latterre composed of chondroitin sulfate and GAGS thatre covalently linked to a core protein. These aggre-ates are then enmeshed in a predominantly type IIollagen matrix. The synovial membrane and synovialuid provide nutritional and mechanical functions.lteration in the composition of synovial fluid isnown to occur in the TMJs of symptomatic patients.he etiology of the altered synovial composition isnclear but it represents a typical inflammatory re-ponse to some inciting event. Inflammatory cyto-ines, proteases, and inhibitors of protease and in-ammatory activity are present. There is also aecrease in the molecular weight of HA because ofhe inflammation.7 The most common etiologies arehought to be macrotrauma, microtrauma, internalerangement, OA, and systemic arthropathy. Theresence of bacteria within the synovial fluid has alsoeen documented, although this remains controver-ial and the clinical significance of this is unclear.8

rrespective of the inciting event, when compensa-ory mechanisms are overcome, inflammation ishought to develop. Not only is the inflammatoryesponse a significant source of pain, but it may leado the development of synovitis, capsulitis, and ulti-ately fibrous adhesions and pseudowalls.9 Internal

erangement may develop secondary to this, or it maye the inciting event. The relation between inflamma-ory changes and internal derangement is, however,

ot well defined. The development of arthrocentesis p

s a therapeutic procedure has also allowed routineynovial fluid sampling. The success of arthrocentesisn many patients with nonspecific arthralgia, internalerangement, and OA may be the result of decreasing

nflammation, eliminating adhesions, or re-establish-ng a normal disc–fossa relation.10-12

he Inflammatory Process

The acute inflammatory process involves an elabo-ate cascade of mediators, and the regulatory mecha-isms are not clearly understood.13 The initial inflam-atory response is thought to involve complement

nd macrophages. Activated macrophages produceany cytokines including interleukin (IL)-1 and tumorecrosis factor-alpha (TNF-alpha). The production ofhese and other cytokines by tissue macrophages ishought to be mediated through nuclear factor kappaeta. Many interleukins that are produced because ofhe inflammatory response have regulatory functions.ndeed, in decreasing order of potency, IL-10, IL-13,L-4, IL-6, and IL-12 possess anti-inflammatory proper-ies. Macrophage-derived cytokines further stimulatendothelial cells to express vascular adhesion mole-ules, such as intercellular adhesion molecule 1 and-selectin. This is thought to facilitate the transmigra-ion of polymorphonuclear leukocytes into the in-amed tissue. Activated endothelial cells also producelatelet-activating factor and IL-8 that further stimu-

ate neutrophils. Tissue destruction ultimately de-ends on the production of free radicals and reactivexygen species by phagocytic cells, such as neutro-hils and macrophages. The principal oxidant gener-ting pathways include nicotinamide adenine dinucle-tide phosphate oxidase and nitric oxide. This results

n the generation of myeloperoxidase, superoxide an-on, ferrous ion (Fe2�), hydrogen peroxide, hydroxyladical, and peroxynitrite anion. Free radicals andeactive oxygen species have been indirectly identi-ed in patients with symptomatic joints.14

Duration of patient symptoms has been evaluateds an outcome predictor after arthrocentesis. Out-omes have not been consistent, with some studieshowing chronicity to adversely effect response toreatment, whereas others have shown this not to behe case.15,16 Symptom chronicity may represent aore complicated chronic inflammatory response

ypified by a frustrated repair process leading to theevelopment of not only fibrous adhesions and OAut also altered peripheral and central neural path-ays for pain perception.

nflammation, Synovitis, and OA

Although inflammation is the central pathologic

rocess of synovitis, the relation between synovitis

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GARY F. BOULOUX 2499

nd OA is not well defined. Subclinical chronic inflam-ation of the synovium, cartilage, and bone in OA is

ecoming increasingly likely.17 The cause of thehronic subclinical inflammation in OA is, however,ot known. The chronic inflammation is associatedith multiple neural changes involving the peripheral

nd central nervous systems. The multitude of inflam-atory mediators within the synovium and synovial

uid contributes to peripheral sensitization. This maye mediated by nerve growth factors that are releaseds part of the inflammatory process. Furthermore,euronal plasticity involves marked changes to cen-ral neural connections and results in central sensiti-ation. Such central changes may persist long afternflammatory changes with the joint have resolved.hronic inflammation also leads to angiogenesis in-olving the synovium, articular cartilage, and bone.ngiogenic factors such as vascular endothelialrowth factor and fibroblast growth factor (FGF) areroduced by lymphocytes in response to inflamma-ory cytokines or hypoxia. Vascular endothelialrowth factor level has been shown to correlate withhe degree of joint effusion on magnetic resonancemaging (MRI) and the degree of synovitis on arthros-opy.18,19 Elevated levels of vascular endothelialrowth factor and FGF have also been identified inatients with internal derangement.20,21 Angiogenesisay also contribute to pain through neurite extension

nd arborization, which are known to occur afterngiogenesis. Perhaps articular structures, which areormally avascular and aneural, become innervatedfter angiogenesis. It is therefore likely that, althoughnflammation develops for unknown reasons, the netesult is a cascade of complex inflammatory processeseading to tissue damage, angiogenesis, neural change,nd pain. Pain and OA, as surrogate markers of inflam-ation, have been shown to correlate with response

o arthrocentesis with instillation of steroid.22,23 Thisurther provides indirect evidence for the potentialole of the inflammatory response in TMJ pain. Al-hough the contribution of the synovium to this in-ammatory process is generally accepted, there is

ncreasing evidence that chondrocytes and fibrochon-rocytes also contribute.24 One key concept is thatechanical stress is transduced to all joint tissues and

ells, resulting in modulation of gene expression andltimately cellular biochemical processes. This pro-ess is most likely generic and the basis for inflamma-ory changes within most joints, including the TMJ.ain, limited function, and tissue destruction occurecondary to a common inflammatory response. It isot clear whether differences in the initiating eventmacrotrauma, microtrauma, internal derangement,ystemic arthropathy, idiopathic, etc) result in quali-ative or quantitative differences in the inflammatory

ediators present. The inflammatory response ulti- b

ately results in tissue destruction, including the lib-ration of the chondroitin-6-sulfate and chondroitin--sulfate GAGS from articular surfaces.25 Theoncentration of these GAGS has been shown to cor-elate with the degree of degenerative change andatient age.26 There is some evidence that rheuma-oid arthritis is associated with the liberation of theame GAGS but in a ratio that is distinct from otheronsystemic causes of joint inflammation.27 Further-ore, when comparing internal derangement withA, differences in the concentration of protein haveeen identified.28 Differences such as these may pro-ide opportunities to use synovial fluid to identify thepecific etiology of the inflammatory process. Thisould allow targeted treatment with potentially betterutcomes.Corticosteroids and HA are frequently used during

rthrocentesis and arthroscopy to modulate inflamma-ion. Corticosteroids have a profound effect on manyiological processes. They are potent anti-inflamma-ory compounds that effectively block phospholipase

2 within cell membranes. As a result, arachidoniccid cannot be formed from membrane phospholip-ds, which ultimately limits the production of multiplenflammatory mediators including prostaglandins,rostacyclins, and leukotrienes. The use of corticoste-oids during arthrocentesis or arthroscopy to de-rease inflammation is, however, still controversial.A, although a normal component of synovial fluid, islso frequently used as an adjunct during arthrocen-esis or arthroscopy to decrease inflammation. HA ishought to have anti-inflammatory properties includ-ng scavenging reactive oxygen species, decreasinghe concentration of inflammatory cytokines, decreas-ng vascular permeability, and inhibiting migration ofnd phagocytosis by polymorphonuclear leuko-ytes.29 There is no evidence-based literature show-ng the superiority of corticosteroid or HA.30,31 Theeneficial effect of both anti-inflammatory drugs fur-her provides indirect evidence of inflammation as aotential player in the development of pain withinhe TMJ.

ynovial Fluid Analysis and the TMJ

There have been many studies over the previous 20ears that have attempted to qualify and quantify inflam-atory mediators in symptomatic and healthy TMJs be-

ore and after arthrocentesis or arthroscopy. Variousechniques of sampling the synovial fluid have beensed, but all rely on the instillation of saline and thespiration of the saline/synovial fluid mix. This tech-ique may not always provide a representative samplef synovial fluid.32 Furthermore, contamination with

lood during arthrocentesis or arthroscopy can interfere

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2500 TMJ PAIN AND SYNOVIAL FLUID ANALYSIS

ith the content and concentration of many synovialuid constituents.33

IL-1beta has been identified in patients with sys-emic arthropathy involving the TMJ.33-35 Further-ore, the IL-1beta concentration correlated with vis-

al analog pain score, capsular tenderness, painhreshold, and joint sounds and degree of anteriorpen bite.34,36 IL-1beta concentration has also beenhown to correlate with the degree of radiographicoint destruction.35 IL-1beta, TNF-alpha, IL-6, and IL-8ave also been measured in symptomatic patientsith disc displacement with reduction, disc displace-ent without reduction, and OA. Levels of all 4 cyto-

ines were significantly higher than in asymptomaticontrols.37 Interestingly, the presence or absence ofisc reduction did not influence cytokine levels, al-hough OA was associated with an increased level ofL-6. Other studies have found higher levels of IL-6 innternal derangement38 and OA.39,40 A possible expla-ation for the increased IL-6 levels in OA is that OAepresents a chronic destructive inflammatory pro-ess, and IL-6, a potent anti-inflammatory cytokine,ay represent a frustrated attempt to modulate dis-

ase progression. IL-6 has also been shown to corre-ate with the degree of synovitis and symptom chro-icity.41-43 The latter may provide indirect evidencehat chronic inflammation plays a role in the patho-hysiology of chronic TMJ pain. Proinflammatoryytokines TNF-alpha, IL-1beta, IL-6, IL-8, and inter-eron-gamma have been found to be present morerequently and in higher concentrations in patientsith TMJ dysfunction compared with controls.44,45

urthermore, the concentrations of TNF-alpha, IL-beta, IL-6, and interferon-gamma have been showno correlate with pain level or radiographic severity ofhe OA. OA is characterized by cartilage and boneestruction, which ultimately relies on osteoclasticctivity. Osteoclastogenesis inhibitor factor/osteopro-egerin is a member of the TNF family that inhibitssteoclast differentiation. Osteoclastogenesis inhibi-or factor/osteoprotegerin has been found to be lowern patients with OA compared with patients withnternal derangement.46,47 This could explain the pro-ressive degenerative changes, mediated by increasedsteoclastic activity, seen in OA. One might expect toee an upregulation of a frustrated reparative processn the face of destructive OA. Indeed, levels of trans-orming growth factor-beta have been shown to bereater in OA compared with internal derangement.48

TNF-alpha has also been measured in patients withystemic arthropathy undergoing arthrocentesis withnstillation of steroid. Levels were measured beforehe initial procedure and again 6 weeks later. Al-hough it was not identified in every patient beforehe procedure, a high pretreatment level of TNF-alpha

as associated with a postprocedure decrease in TNF- a

lpha and elimination of pain.49 TNF-alpha has alsoeen identified in patients with unilateral signs andymptoms consistent with capsulitis and synovitis.50

atients underwent bilateral arthrocentesis with instil-ation of steroid with the asymptomatic joint servings the control. Levels of TNF-alpha were measuredefore and immediately after the arthrocentesis butefore steroid was injected. Significantly higher pre-reatment levels of TNF-alpha were identified in theymptomatic joints, and TNF-alpha levels were signif-cantly lower after the procedure. A strong correla-ion among capsulitis, synovitis, and TNF-alpha levelas also been identified by others.51 Soluble TNFsave also been measured and found in higher concen-rations in internal derangement and OA when com-ared with controls.52 In another study, TNF-alpha,

L-1beta, IL-6, and IL-8 were measured before arthro-entesis in a cohort of patients with internal derange-ent.53 Inflammatory mediators were not identified

n all patients. Unsuccessful cases were associatedith increased detection of IL-6 and increased con-

entration of IL-1beta. This apparent paradigm of anncreased anti-inflammatory and proinflammatory cy-okine within the same inflammatory response repre-ents normal homeostasis, which typically dictateshat regulatory and counter-regulatory pathways pro-eed simultaneously.Free radicals and reactive oxygen species are

hought to be key players in the inflammatory pro-ess. Nitric oxide concentration has been measured inatients with internal derangement and OA undergo-

ng arthroscopy and found to be significantly elevatedompared with healthy controls.54 Furthermore, ni-ric oxide concentration correlated with global paincores and the arthroscopic severity of OA. Nitrite,itrate, and thiobarbituric acid-reactive substance lev-ls, which serve as indirect markers of reactive oxy-en species, have also been identified in patients withnternal derangement.55 Patients were treated withrthrocentesis alone or arthrocentesis and instillationf HA. Interestingly, although all patients had symp-omatic improvement in their pain, only patients un-ergoing arthrocentesis with HA showed decreased

evels of these biomarkers. This may provide indirectvidence supporting the anti-inflammatory propertiesf HA. Circumstantial evidence to support the iron-ependent generation of free radicals and the devel-pment of modified synovial proteins in symptomaticMJs has also been reported.56 Free radicals and re-ctive oxygen species may initiate or perpetuate jointnflammation and contribute to tissue destruction.

Bradykinin, leukotriene B4, prostaglandin E2, andubstance P have also been identified in patients withnternal derangement and OA before arthrocentesis.atients who responded poorly to the procedure, as

ssessed with serial visual analog pain scores, had

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GARY F. BOULOUX 2501

igher detection rates of all mediators and signifi-antly higher concentrations of bradykinin.57 Brady-inin and leukotriene B4 have also been shown toorrelate with the degree of synovitis.58 However,thers have found that bradykinin correlates poorlyith clinical signs and symptoms.59 The severity of

nternal derangement, as classified according to theilkes criteria, has been shown to correlate with

evels of prostaglandin E2, leukotriene B4, malondial-ehyde, nitric oxide, and myeloperoxidase.60 The ex-ression of substance P within the synovium of patientsith internal derangement undergoing arthroscopy has

lso been compared with healthy controls.61 Expressionas significantly increased, although, surprisingly,

here was no correlation with pain or the arthro-copic grade of synovitis. Beta-endorphin levels havelso been measured in subjects with normal TMJs andubjects with TMJ dysfunction. The concentration ofeta-endorphin was higher in the subjects with TMJysfunction, although it did not correlate with pain

evel.62 Specific pain mediators, such as neuropeptide, serotonin, calcitonin gene-related peptide, and cap-aicin receptor transient receptor potential vanilloid-1ave also been identified with symptomatic TMJs andorrelate with pain level or degree of synovitis.63-65

Receptor activator of nuclear factor kappa betaigand (RANKL) is a surrogate marker for osteoclasticctivity and has been measured in patients with inter-al derangement and OA undergoing arthroscopy.66

xpression of this marker was seen in synovial cells,ndothelial cells, and fibroblasts, although there waso correlation with the arthroscopic grade of synovi-is or OA. FGF-2, as a marker of tissue repair, has alsoeen measured in patients with internal derangementndergoing arthrocentesis.67 The rate of detectionnd the concentration of FGF-2 were increased com-ared with asymptomatic controls. Interestingly,GF-2 was not detected in all patients. This may rep-esent inadequate synovial fluid sampling or FGF-2evels that are below the current detection threshold.omplete absence of FGF-2 and, hence, any active

epair process would be unlikely given an inflamma-ory response or even normal tissue turnover.

The relation between joint effusion on MRI andynovial fluid composition has also been investigated.ymptomatic joints with an effusion were comparedith symptomatic joints without an effusion. Joint

ffusion was found to be associated with an overallncrease in protein content and IL-6 level.68,69 There

as, however, no difference in the concentrations ofNF-alpha, IL-1beta, or IL-8. Similar concentrations of

hese inflammatory mediators in both groups mayuggest that MRI lacks the sensitivity to detect smallerffusions that are present in many symptomatic joints.he presence of an effusion on MRI would appear to

ave a relatively strong predictive value for the pres- e

nce of protein and inflammatory mediators. Indeed,oint effusion correlates with increased protein andain.70,71 However, effusions on MRI may be seennly in about 10% of symptomatic patients.72 Contin-ed pain, an indicator of an unsuccessful outcomefter arthrocentesis, has been shown to correlate withigher initial protein levels.73 In summary, MRI, al-hough not sensitive for detecting joint effusion, has atrong positive predictive value for joint inflamma-ion.

Protease activity, mediated specifically through ma-rix metalloproteinases, has also been identified inatients with TMJ dysfunction.74 No correlation be-ween protease concentration and pain was identi-ed. Products of protease degradation have been

dentified in patients 6 months after discectomy with-ut replacement.75 Cartilage fragments of oligomericatrix protein and aggrecan were identified. These

ragments are products of normal articular cartilageurnover but have been shown to be present in higheroncentrations in OA and rheumatoid arthritis. Exper-mentally induced OA in sheep has been shown to bessociated with increased chondroitin sulfate and de-reased HA concentrations.76 This represents degra-ation of normal proteins, proteoglycans, and GAGS

n response to inflammatory mediators, free radicals,nd reactive oxygen species. Counter-regulatory me-iators such as tissue inhibitor of metalloproteinase-1,n inhibitor of matrix metalloproteinase, have alsoeen shown to be present and correlate with chro-icity, pain, radiographic evidence of degenerativehanges, and IL-6 levels.41

In conclusion, the pathophysiology of pain andimited function in patients with temporomandibularysfunction is not clearly understood. However, theole of inflammation in this process is becoming in-reasingly clear. The inflammatory process is a com-licated series of biochemical pathways whose ulti-ate goal is to produce pain, limit function, and

nitiate a reparative process. This is a common themepplicable to all injured tissues. Different inflamma-ory mediators have been identified in synovial fluid.here is evidence that some mediator levels correlateith pain, chronicity, severity of degenerative change,

nd response to treatment. However, the potential in-dequacies of sampling techniques for TMJ synovialuid analysis and limitations with the sensitivity ofssays used to detect synovial fluid constituents makenterpretation of these results difficult. Sufficient evi-ence exists to conclude that inflammation is present

n most symptomatic TMJs. The contribution thatnflammation plays in the perpetuation of pain is

uch less obvious. Clearly there are many patientsho respond to procedures such as arthrocentesis

nd arthroscopy, a major objective of which is the

limination of inflammation. Other patients continue

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2502 TMJ PAIN AND SYNOVIAL FLUID ANALYSIS

o experience pain and limited function despite treat-ent, and the pathophysiology of the pain may beore complicated.The etiology of TMJ pain is multifactorial, although

he common pathway likely involves inflammation forany patients. The potential for synovial fluid analysis

o determine etiology does not currently exist. Thisould potentially provide enormous benefit in thatot only could the inflammatory process be identifiednd treated therapeutically, but the inciting mecha-ism of joint injury could also be identified. In theoryhis might allow systemic arthropathy, internal de-angement, synovitis, capsulitis, fibrous adhesions,nd OA to be distinguished based on not only poten-ial differences in inflammatory mediators but alsoualitative and quantitative differences in synovialuid degradation products. It is possible, however,hat inflammation results in a common pathway ofissue breakdown, with similar synovial fluid compo-ition irrespective of the inciting event. This mayecessitate a more traditional and empiric approacho managing TMJ pain but with a better understandingf a common inflammatory pathway.

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2. Emshoff R: Clinical factors affecting the outcome of arthrocen-tesis and hydraulic distension of the temporomandibular joint.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100:409,2005

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4. Weinberg B, Fermor B, Guilak F: Nitric oxide synthase andcyclooxygenase interactions in cartilage and meniscus: Rela-tionship to joint physiology, arthritis and tissue repair, in Har-ris, R (ed): Inflammation in the Pathogenesis of Chronic Dis-eases, vol 31. New York, Springer-Verlag, 2007

5. Okazaki J, Kakudo K, Kamada A, et al: Chondroitin sulfateisomers in synovial fluid of healthy and diseased human tem-poromandibular joints. Eur J Oral Sci 105:440, 1997

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7. Shibata T, Murakami K, Kubota E, et al: Glycosaminoglycancomponents in temporomandibular joint synovial fluid as mark-ers of joint pathology. J Oral Maxillofac Surg 56:209, 1998

8. Kaneyama K, Segami N, Sun W, et al: Analysis of tumor necrosisfactor-a, interleukin-6, soluble tumor necrosis factor receptorsI and II, interleukin-6 soluble receptor, interleukin-1 solublereceptor type II, interleukin-1 receptor antagonist, and proteinin the synovial fluid of patients with temporomandibular jointdisorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod99:276, 2005

9. Hirota W: Intra-articular injection of hyaluronic acid reducestotal amounts of leukotriene C4, 6-keto-prostaglandin F1-�,prostaglandin F2-� and interleukin-1� in synovial fluid of pa-tients with internal derangement in disorders of the temporo-mandibular joint. Br J Oral Maxillofac Surg 36:35, 1998

0. Kopp S, Wenneberg B, Haraldson T, et al: The short term effectof intra-articular injections of sodium hyaluronate and cortico-steroids on temporomandibular joint pain and dysfunction.

J Oral Maxillofac Surg 43:429, 1985

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2. Aghabeigi B, Cintra N, Meghji S, et al: Temporomandibularjoint synovial sampling: Estimation of dilutional factor usingcalcium ion concentration. Int J Oral Maxillofac Surg 31:646,2002

3. Alstergren P, Kopp S, Theodorsson E: Synovial fluid samplingfrom the temporomandibular joint: Sample quality criteria andlevels of interleukin-1� and serotonin. Acta Odontol Scand57:16, 1999

4. Alstergren P, Ernberg M, Kvarnstrom M, et al: Interleukin-1� insynovial fluid from the arthritic temporomandibular joint andits relation to pain, mobility, and anterior open bite. J OralMaxillofac Surg 56:1059, 1998

5. Nordahl S, Alstergren P, Eliasson S, et al: Interleukin-1� inplasma and synovial fluid in relation to radiographic changes inarthritic temporomandibular joints. Eur J Oral Sci 106:559,1998

6. Suzuki T, Segami N, Kaneyama K, et al: Specific expression ofinterleukin-1� in temporomandibular joints with internal de-rangement: Correlation with clinical findings. Oral Surg OralMed Oral Pathol Oral Radiol Endod 88:413, 1999

7. Kaneyama K, Segami N, Nishimura M, et al: Importance ofproinflammatory cytokines in synovial fluid from 121 jointswith temporomandibular disorders. Br J Oral Maxillofac Surg40:418, 2002

8. Sato J, Segami N, Nishimura M, et al: Expression of interleukin6 in synovial tissues in patients with internal derangement ofthe temporomandibular joint. Br J Oral Maxillofac Surg 41:95,2003

9. Kubota E, Kubota T, Matsumoto J, et al: Synovial fluid cytokinesand proteinases as markers of temporomandibular joint dis-ease. J Oral Maxillofac Surg 56:192, 1998

0. Kaneyama K, Segami N, Sato J, et al: Interleukin-6 family ofcytokines as biochemical markers of osseous changes in thetemporomandibular joint disorders. Br J Oral Maxillofac Surg42:246, 2004

1. Shinoda C, Takaku S: Interleukin-1�, interleukin-6, and tissueinhibitor of metalloproteinase-1 in the synovial fluid of thetemporomandibular joint with respect to cartilage destruction.Oral Dis 6:383, 2000

2. Nishimura M, Segami N, Kaneyama K, et al: Proinflammatorycytokines and arthroscopic findings of patients with internalderangement and osteoarthritis of the temporomandibularjoint. Br J Oral Maxillofac Surg 40:68, 2002

3. Sandler N, Buckley M, Cillo J, Braun T: Correlation of inflam-matory cytokines with arthroscopic findings in patients withtemporomandibular joint internal derangements. J Oral Maxil-lofac Surg 56:534, 1998

4. Kacena M, Merrel G, Konda S, et al: Inflammation and bonychanges at the temporomandibular joint. Cells Tissues Organs169:257, 2001

5. Sato J, Segami N, Nishimura M, et al: Expression of interleukin8 in synovial tissues in patients with internal derangement ofthe temporomandibular joint and its relationship with clinicalvariables. Oral Surg Oral Med Oral Pathol Oral Radiol Endod103:467, 2007

6. Kaneyama K, Segami N, Sato J, et al: Expression of osteopro-tegerin in synovial tissue and degradation of articular cartilage:Comparison with arthroscopic findings of temporomandibularjoint disorders. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 96:258, 2003

7. Kaneyama K, Segami N, Nishimura M, et al: Osteoclastogenesisinhibitory factor/osteoprotegerin in synovial fluid from pa-tients with temporomandibular disorders. Int J Oral MaxillofacSurg 32:404, 2003

8. Ping-Ke F, Xu-Chen M, Da-Long M, et al: Determination ofinterleukin-1 receptor antagonist, interleukin-10, and trans-forming growth factor-�1 in synovial fluid aspirates of patientswith temporomandibular disorders. J Oral Maxillofac Surg 57:922, 1999

9. Fredriksson L, Alstergren P, Kopp S: Tumor necrosis factor-a in

temporomandibular joint synovial fluid predicts treatment ef-

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0. Emshoff R, Puffer P, Strobl H, Gabner R: Effect of temporoman-dibular joint arthrocentesis on synovial fluid mediator level oftumor necrosis factor-�: Implications for treatment outcome.Int J Oral Maxillofac Surg 29:176, 2000

1. Emshoff R, Puffer P, Rudisch A, Gabner R: Temporomandibularjoint pain: Relationship to internal derangement type, osteoar-throsis, and synovial fluid mediator level of tumor necrosisfactor-�. Oral Surg Oral Med Oral Pathol Oral Radiol Endod90:442, 2000

2. Uehara J, Kuboki T, Fujisawa T, et al: Soluble tumour necrosisfactor receptors in synovial fluids from temporomandibularjoints with painful anterior disc displacement without reduc-tion and osteoarthritis. Arch Oral Biol 49:133, 2004

3. Nishimura M, Segami N, Kaneyama K, et al: Comparison ofcytokine level in synovial fluid between successful and unsuc-cessful cases in arthrocentesis of the temporomandibular joint.J Oral Maxillofac Surg 62:284, 2004

4. Takahashi T, Kondoh T, Ohtani T, et al: Association betweenarthroscopic diagnosis of temporomandibular joint osteoarthri-tis and synovial fluid nitric oxide levels. Oral Surg Oral MedOral Pathol Oral Radiol Endod 88:129, 1999

5. Alpaslan C, Bilgihan A, Alpaslan G, et al: Effect of arthrocentesisand sodium hyaluronate injection on nitrite, nitrate and thio-barbituric acid-reactive substance levels in the synovial fluid.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89:686, 2000

6. Zardeneta G, Milam S, Schmitz J: Iron-dependent generation offree radicals: Plausible mechanisms in the progressive deterio-ration of the temporomandibular joint. J Oral Maxillofac Surg58:302, 2000

7. Kaneyama K, Segami N, Sato J, et al: Prognostic factors inarthrocentesis of the temporomandibular joint: Comparison ofbradykinin, leukotriene B4, prostaglandin E2, and substance Plevel in synovial fluid between successful and unsuccessfulcases. J Oral Maxillofac Surg 65:242, 2007

8. Nishimura M, Segami N, Kaneyama K, et al: Relationshipsbetween pain related mediators and both synovitis and jointpain in patients with internal derangements and osteoarthritisof the temporomandibular joint. Oral Surg Oral Med OralPathol Oral Radiol Endod 94:328, 2002

9. Kaneyama K, Segami N, Nishimura M, et al: The ideal lavagevolume for removing bradykinin, interleukin-6, and proteinfrom the temporomandibular joint by arthrocentesis. J OralMaxillofac Surg 62:657, 2004

0. Arinci A, Ademoglu E, Aslan A, et al: Molecular correlates oftemporomandibular joint disease. Oral Surg Oral Med OralPathol Oral Radiol Endod 99:666, 2005

1. Sato J, Segami N, Yoshitake Y, et al: Specific expression ofsubstance P in synovial tissues of patients with symptomatic,non-reducing internal derangement of the temporomandibularjoint: Comparison with clinical findings. Br J Oral MaxillofacSurg 45:372, 2007

2. Kajii T, Okamoto T, Yura S, et al: Elevated levels of �-endorphinin temporomandibular joint synovial lavage fluid of patientswith closed lock. J Orofac Pain 19:41, 2005

3. Sato J, Segami N, Yoshitake Y, et al: Expression of capsaicinreceptor TRPV-1 in synovial tissues of patients with symptom-atic internal derangement of the temporomandibular joint andjoint pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod100:674, 2005

4. Kopp S: The influence of neuropeptides, serotonin, and inter-leukin 1� on temporomandibular joint pain and inflammation.J Oral Maxillofac Surg 56:189, 1998

5. Sato J, Segami N, Kaneyama K, et al: Relationship of calcitoningene-related peptide in synovial tissues and temporomandibu-lar joint pain in humans. Oral Surg Oral Med Oral Pathol OralRadiol Endod 98:533, 2004

6. Kaneyama K, Segami N, Sato J, et al: Expression of receptoractivator of nuclear factor-kappa B ligand in synovial tissue:Comparison with degradation of articular cartilage in temporo-mandibular joint disorders. Oral Surg Oral Med Oral Pathol Oral

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7. Sato J, Segami N, Kaneyama K, et al: Levels of fibroblast growthfactor 2 in synovial fluids in human patients with internalderangement of the temporomandibular joint. Oral Surg OralMed Oral Pathol Oral Radiol Endod 96:673, 2003

8. Segami N, Miyamaru M, Nishimura M, et al: Does joint effusionon T2 magnetic resonance images reflect synovitis? Part 2.Comparison of concentration levels of pro-inflammatory cyto-kines and total protein in synovial fluid of the temporomandib-ular joint with internal derangements and osteoarthrosis. OralSurg Oral Med Oral Pathol Oral Radiol Endod 94:515, 2002

9. Guler N, Uckan S, Imirzalioglu P, et al: Temporomandibularjoint internal derangement: Relationship between joint painand MR grading of effusion and total protein concentration inthe joint fluid. Dentomaxillofac Radiol 34:175, 2005

0. Takahashi T, Nagai H, Seki H, et al: Relationship between jointeffusion, joint pain, and protein levels in joint lavage fluid ofpatients with internal derangement and osteoarthritis of thetemporomandibular joint. J Oral Maxillofac Surg 57:1187, 1999

1. Westesson P, Brooks S: Temporomandibular joint: Relationshipbetween MR evidence of effusion and the presence of pain and

disc displacement. Am J Radiol 159:559, 1992

2. Larheim T, Katzberg R, Westesson P, et al: MR evidence oftemporomandibular joint fluid and condyle marrow alterations:Occurrence in asymptomatic volunteers and symptomatic pa-tients. Int J Oral Maxillofac Surg 30:113, 2001

3. Kaneyama K, Segami N, Sun W, et al: Levels of soluble cytokinefactors in temporomandibular joint effusions seen on magneticresonance images. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 99:411, 2005

4. Zardeneta G, Milam S, Lee T, et al: Detection and preliminarycharacterization of matrix metalloproteinase activity in tem-poromandibular joint lavage fluid. Int J Oral Maxillofac Surg27:397, 1998

5. Flygare L, Wendel M, Saxne T, et al: Cartilage matrix mac-romolecules in lavage fluid of temporomandibular jointsbefore and 6 months after diskectomy. Eur J Oral Sci 105:369, 1997

6. Ishimaru J, Ogi N, Mizuno S, Goss A: Quantitation of chon-droitin-sulfates, disaccharides and hyaluronan in normal, earlyand advanced osteoarthritic sheep temporomandibular joints.

Osteoarthritis Cartilage 9:365, 2001