Inflammatory mediators related to arthrogenic temporomandibular dysfunctions

Rodrigo Lorenzi Poluha Eduardo Grossmann About the authors

ABSTRACT

BACKGROUND AND OBJECTIVES:

Inflammatory disorders of the temporomandibular joint present a high prevalence in the population. The knowledge about inflammatory mediators, such as histamine, serotonin, kinins, eicosanoids, platelet-activating factor, nitric oxide, tumor necrosis factor and interleukins, may contrib-goupute to a better understanding of these disorders. The objective of this study was to review the literature on the major inflammatory mediators involved in temporomandibular arthralgia.

CONTENTS:

A search was made in the LILACS, Pubmed/Medline, Scielo and Science direct databases, crossing the following descriptors in the English and Portuguese language: inflammation, temporomandibular joint, inflammatory mediators, inflammation, temporomandibular joint and inflammatory mediators. Articles of literature review, systematic review, meta-analysis and randomized clinical trials, as well as books with compatible themes, published between September 1990 and June 2017 were included. Clinical reports, open label studies, animal model studies, were excluded.

CONCLUSION:

The knowledge of the inflammatory process, with the different mediators and mechanisms, can contrib-goupute to a better understanding, allowing the selection of the best therapy to be used clinically in cases of arthrogenic temporomandibular joint disorders.

Keywords:
Inflammation; Inflammatory mediators; Temporomandibular joint disorder

RESUMO

JUSTIFICATIVA E OBJETIVOS:

As desordens inflamatórias da articulação temporomandibular apresentam alta prevalência na população. O conhecimento sobre os mediadores inflamatórios, tais como histamina, serotonina, cininas, eicosanoides, fator de ativação plaquetária, óxido nítrico, fator de necrose tumoral e interleucinas, pode contribuir para melhor entendimento dessas desordens. O presente trabalho objetivou revisar a literatura a respeito dos principais mediadores inflamatórios envolvidos nas artralgias temporomandibulares.

CONTEÚDO:

Foi realizada uma busca nas bases de dados LILACS, Pubmed/Medline, Scielo e Science direct, cruzando-se os seguintes descritores em língua inglesa e portuguesa: inflammation, temporomandibular joint, inflammatory mediators, inflamação, articulação temporomandibular e mediadores inflamatórios. Foram incluídos artigos de revisão de literatura, revisão sistemática, meta-análise e estudos clínicos randomizados, bem como livros com temática compatível, publicados no período de setembro de 1990 a junho de 2017. Foram excluídos casos clínicos, estudos abertos «open-label» e estudos em modelos animais.

CONCLUSÃO:

O conhecimento do processo inflamatório, com os diferentes mediadores e mecanismos, pode contribuir para um melhor entendimento do mesmo, possibilitando a seleção da melhor terapêutica para ser empregada clinicamente nos casos de artralgias temporomandibulares.

Descritores:
Inflamação; Mediadores inflamatórios; Transtornos da articulação temporomandibular

INTRODUCTION

Temporomandibular dysfunction (TMD) is a set of functional and pathological changes that affect the masticatory muscles, associated structures, and the temporomandibular joint (TMJ)1.1 Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache. 2014;28(1):6-27. The TMJ is considered a ginglymoarthrodial joint that allows rotational and translational motion. These movements are essential in mastication, speech, and swallowing22 Okeson JP. Joint intracapsular disorders: diagnostic and nonsurgical management considerations. Dent Clin North Am. 2007;51(1):85-103.,33 Wadhwa S, Kapila S. TMJ disorders: future innovations in diagnostics and therapeutics. J Dent Educ. 2008;72(8):930-47..

TMJ inflammatory disorders have a 34.2% prevalence in the population44 Manfredini D, Guarda-Nardini L, Winocur E, Piccotti F, Ahlberg J, Lobbezoo F. Research diagnostic criteria for temporomandibular disorders: a systematic review of axis I epidemiologic findings. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112(4):453-62.. It can occur due to trauma or an intrinsic and/or extrinsic joint overload that exceeds the adaptive capacity of the joint tissues, generating an inflammation as a consequence55 Carrara SV, Conti PC, Barbosa JS. Termo do 1º Consenso em Disfunção Temporomandibular e Dor Orofacial. Dental Press J Orthod. 2010;15(3):114-20.,66 Young AL. Internal derangements of the temporomandibular joint: a review of the anatomy, diagnosis, and management. J Indian Prosthodont Soc. 2015;15(1):2-7.. Inflammation is a set of homeostatic phenomena in the vascularized tissues to remove harmful agents and to restore their normal functions. These phenomena are coordinated by the action of inflammation mediators (IM)77 Brunton LL, Chabner BA, Knollman BA. As Bases Farmacológicas da Terapêutica de Goodman e Gilman. 12ª ed. McGraw Hill; 2012. 563-600p.

8 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.
-99 Rahmati M, Mobasheri A, Mozafari M. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the art, current prospects, and future challenges. Bone. 2016;81-90.. Histamine, serotonin, kinins, eicosanoids, platelet activating factor, nitric oxide, tumor necrosis factor, and interleukins are among the main IM of TMJ disorders1010 Bouloux GF. Temporomandibular joint pain and synovial fluid analysis: a review of the literature. J Oral Maxillofac Surg. 2009;67(11):2497-504.,1111 Ernberg M. The role of molecular pain biomarkers in temporomandibular joint internal derangement. J Oral Rehabil. 2017;44(6):481-91..

Therefore, understanding these IM can contrib-goupute to a better understanding the disorders, as well as to select the proper therapy, as the anti-inflammatory pharmacology, intra-articular injections, arthrocentesis, and arthroscopy1212 Wieckiewicz M, Boening K, Wiland P, Shiau YY, Paradowska-Stolarz A. Reported concepts for the treatment modalities and pain management of temporomandibular disorders. J Headache Pain. 2015;16:106.,1313 Hosgor H, Bas B, Celenk C. A comparison of the outcomes of four minimally invasive treatment methods for anterior disc displacement of the temporomandibular joint. Int J Oral Maxillofac Surg. 2017;46(11):1403-10., in order to optimize the clinical outcome.

The objective of the present study was to review the literature about the main IM involved in temporomandibular arthralgia.

CONTENTS

Literature search strategies

A search was conducted in the LILACS, Pubmed/Medline, Scielo, and Science direct databases, crossing the following keywords in English and in Portuguese: "inflammation", "inflammation mediators", "temporomandibular joint" "temporomandibular joint disorders," "inflamação", "mediadores da inflamação", "articulação temporomandibular" and "transtornos da articulação temporomandibular". We included review articles, systematic review, meta-analysis and randomized clinical studies, as well as books on compatible themes published from September 1990 to June 2017. Reports of clinical cases, "open-label" studies, studies with animal models were excluded. We found a total of 95 study materials (articles and books). Of these, after reading the summary, 50 articles and 6 books met the inclusion criteria and provided the basis for the writing of the present study.

Inflammatory joint disorders of the temporomandibular joint

It is a series of alterations in which some tissues that compose the joint structure suffer an inflammatory process, being classified according to the structures affected in synovitis, capsulitis, retrodiscitis, ligamentitis, and arthritis1414 Okeson JP. Tratamento das desordens temporomandibulares e oclusão. 7ª ed. Mosby Elsevier; 2013. 154-5p.,1515 Valle RT, Grossmann E, Fernandes RSM. Disfunções Temporomandibulares: Abordagem Clínica. 1ª ed. Napoleão; 2015. 80-102p.. Usually, it is difficult to make a differential diagnosis of these arthrogenic alterations due to their clinical similarities1616 Gynther GW, Dijkgraaf LC, Reinholt FP, Holmlund AB, Liem RS, de Bont LG. Synovial inflammation in arthroscopically obtained biopsy specimens from the temporomandibular joint: a review of the literature and a proposed histologic grading system. J Oral Maxillofac Surg. 1998;56(11):1281-6..

The inflammation of the synovial membrane that lines the TMJ (synovitis) results in changes in the composition and amount of the synovial fluid1717 Israel HA. Internal derangement of the temporomandibular joint: new perspectives on an old problem. Oral Maxillofac Surg Clin North Am. 2016;28(3):313-33.. Clinically, it is characterized by a persistent intracapsular pain that is intensified with the jaw movement1414 Okeson JP. Tratamento das desordens temporomandibulares e oclusão. 7ª ed. Mosby Elsevier; 2013. 154-5p.. When intense, necrosis and fibrin deposition in the joint surface may occur which reduces the joint space and eventually leading to a TMJ fibrous ankylosis1818 de Bont LG, Dijkgraaf LC, Stegenga B. Epidemiology and natural progression of articular temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83(1):72-6..

The inflammation of the TMJ capsular ligament (capsulitis), is clinically manifested by pain on palpation of the lateral head pole of the jaw when in static joint position and in motion. The most frequent etiologic factor is the macro trauma when the capsular ligament is abruptly stretched1414 Okeson JP. Tratamento das desordens temporomandibulares e oclusão. 7ª ed. Mosby Elsevier; 2013. 154-5p.,1515 Valle RT, Grossmann E, Fernandes RSM. Disfunções Temporomandibulares: Abordagem Clínica. 1ª ed. Napoleão; 2015. 80-102p.. During the healing process, the joint capsule can adhere to adjacent structures (adhesive capsulitis) or heal with loss of length (capsular fibrosis1818 de Bont LG, Dijkgraaf LC, Stegenga B. Epidemiology and natural progression of articular temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83(1):72-6..

The inflammation of the TMJ retrodiscal tissue (retrodiscitis) is characterized by a pulsating pain1515 Valle RT, Grossmann E, Fernandes RSM. Disfunções Temporomandibulares: Abordagem Clínica. 1ª ed. Napoleão; 2015. 80-102p., which can lead to acute malocclusion in the contralateral anterior jaw due to local edema. Macro and microtrauma that force the mandibular condyle towards the innervated and vascularized retrodiscal tissues may cause a retrodiscitis1414 Okeson JP. Tratamento das desordens temporomandibulares e oclusão. 7ª ed. Mosby Elsevier; 2013. 154-5p.. The intensity of the trauma and the progression of the inflammatory process can cause the perforation of retrodiscal tissues and put the mandibular condyle in direct contact with the mandibular fossa1818 de Bont LG, Dijkgraaf LC, Stegenga B. Epidemiology and natural progression of articular temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83(1):72-6..

The inflammation of the disc ligaments (ligamentitis) is a result of macro or microtrauma, bruxism and/or functional acts of broad magnitude in an attempt to move the disc of the mandibular condyle. Usually, it results in intermittent pain, increasing by maximum intercuspation and reducing by the interposition of a dental spatula. It can be associated with pain, protective muscle co-contraction, and limitation of jaw movements1414 Okeson JP. Tratamento das desordens temporomandibulares e oclusão. 7ª ed. Mosby Elsevier; 2013. 154-5p..

The inflammation of the joint surfaces (arthritis) is a group of disorders in which we observe changes in the morphology of the bone tissue. Several types of arthritis can impact the TMJ (osteoarthritis, osteoarthrosis, and polyarthritis). The level of pain and the clinical and image findings vary tremendously in the different types1414 Okeson JP. Tratamento das desordens temporomandibulares e oclusão. 7ª ed. Mosby Elsevier; 2013. 154-5p..

INFLAMMATION MEDIATORS

Inflammation mediators are substances released in an injured tissue area or by properly activated cells that coordinate the process of the inflammatory response1919 Oliveira Junior JO, Portella Junior CS, Cohen CP. Inflammatory mediators of neuropathic pain. Rev Dor. 2016;17(Suppl 1):35-42. (Table 1).

Table 1
Summary of the key inflammation mediators found in arthrogenic temporomandibular dysfunctions

Histamine

Histamine is a vasoactive amine formed by the histidine decarboxylation by the l-histidine enzyme decarboxylase, found in the mast cells, basophils, platelets, cells of the human epidermis, gastric mucosa, and neurons of the central nervous system (CNS)2020 Yagiela JA, Dowd FJ, Johnson B, Mariotti A. Farmacologia e Terapêutica para Dentistas. 6ª ed. Mosby Elsevier; 2011. 318-52p.. The tissue aggression leads to the degranulation of the mast cells88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p., usually found in the retrodiscal zone and contrib-gouputes to the TMJ inflammation mainly through the release of histamine2121 Henry CH, Wolford LM. Substance P and mast cells: preliminary histologic analysis of the human temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92(4):384-9.. In the inflammatory process, histamine promotes the vasodilation, increasing vascular permeability, and endothelial activation, and its effects are mediated by the interaction with four receptors (H1, H2, H3, and H4). H1 receptors are essentially found in blood vessels, and they promote vasodilation, bronchoconstriction, and modulation of the circadian rhythm. H2 receptors are in the intestine and induce the secretion of gastric acid. The H3 predominates in the CNS acting as neurotransmitters. H4 is widely expressed in the bone marrow and leukocytes and mediates the mast cells chemotaxis77 Brunton LL, Chabner BA, Knollman BA. As Bases Farmacológicas da Terapêutica de Goodman e Gilman. 12ª ed. McGraw Hill; 2012. 563-600p.. Following one to two hours after the aggression, the receptors of the endothelial cells become hyposensitive to the histamine action, and the exudative phenomena continue by other mediators88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. Histamine inactivation occurs by for methylation in the liver, or oxidation in the kidneys and intestines through histaminase77 Brunton LL, Chabner BA, Knollman BA. As Bases Farmacológicas da Terapêutica de Goodman e Gilman. 12ª ed. McGraw Hill; 2012. 563-600p.. Histamine concentration tends to be higher in patients with osteoarthritis than with other TMJ disorders, having, in addition, a positive correlation between the pain and the concentration of this amine2222 Li W, Long X, Jiang S, Li Y, Fang W. Histamine and substance P in synovial fluid of patients with temporomandibular disorders. J Oral Rehabil. 2015;42(5):363-9.. Histamine induces the nociception through an indirect mechanism stimulating the 5-hydroxytryptamine release (5-HT, serotonin)2323 Ting E, Roveroni RC, Ferrari LF, Lotufo CM, Veiga MC, Parada CA, et al. Indirect mechanism of histamine-induced nociception in temporomandibular joint of rats. Life Sci. 2007;81(9):765-71..

Serotonin (5-HT)

5-HT is an amine found in the animal and vegetal kingdoms. It is synthesized in the serotonergic neurons of the CNS and in the enterochromaffin cells (Kulchitsky cells) of the gastrointestinal tract of the animals. In the human body, 5-HT is synthesized from the tryptophan amino acid by short metabolic pathway, that involves two enzymes: tryptophan hydroxylase and aromatic L-amino acid descarboxylase77 Brunton LL, Chabner BA, Knollman BA. As Bases Farmacológicas da Terapêutica de Goodman e Gilman. 12ª ed. McGraw Hill; 2012. 563-600p.. Although being better known by its action as a neurotransmitter in the CNS, 5-HT contrib-gouputes to vasodilation and the increase of vascular permeability, in inflammation, being released by platelets (that take 5-TH from of the circulation, storing in secretory granules by active transport) at the moment of its aggregation2424 Wannamacher L, Ferreira MBC. Farmacologia Clínica para Dentistas. 3ª ed. Guanabara Koogan; 2007. 129-43p.. The levels of 5-HT in the synovial fluid of the temporomandibular arthralgias, in patients with arthritis, show that it is significantly increased and related to pain during the movement of the joint and the reduction of the mandibular mobility2525 Alstergren P, Kopp S. Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints. Pain. 1997;72(2):137-43.. 5-HT also induces nociception in the TMJ region by the activation ofb1 andb2 adrenoreceptors located in this joint, and also the local release of adrenergic amines and prostaglandins. Therefore, high levels of 5-HT in the synovial fluid of patients with TMJ inflammatory pain can contrib-goupute to the maintenance of the painful picture2626 Oliveira-Fusaro MC, Clemente-Napimoga JT, Teixeira JM, Torres-Chávez KE, Parada CA, Tambeli CH. 5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local b adrenoceptors. Pharmacol Biochem Behav. 2012;102(3):458-64..

Kinins

Kinins (bradykinin, lysyl-bradykinin, and methionyl-lysyl-bradykinin) keep the exudative phenomena after the hypersensitization to histamine, with effectiveness 10 times higher88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. Kinins interact with specific receptors (B1 and B2), present in inflammatory cells, like macrophages, promoting the synthesis of interleukin-1 and the tumor necrosis factor (TNF) (when coupled to B1) receptors, activating A2 and C phospholipases (when coupled to B2receptors)2424 Wannamacher L, Ferreira MBC. Farmacologia Clínica para Dentistas. 3ª ed. Guanabara Koogan; 2007. 129-43p.. Bradykinin has been implied in the pathogenesis of the TMJ inflammatory conditions due to its pro-inflammatory properties2727 Suzuki T, Segami N, Nishimura M, Sato J, Nojima T. Bradykinin expression in synovial tissues and synovial fluids obtained from patients with internal derangement of the temporomandibular joint. Cranio. 2003;21(4):265-70.. The increase of bradykinin levels in the synovial fluid of patients with temporomandibular dysfunction (TMD) can indicate the lower effectiveness of using arthrocentesis in this joint2828 Kaneyama K, Segami N, Sato J, Fujimura K, Nagao T, Yoshimura H. Prognostic factors in arthrocentesis of the temporomandibular joint: comparison of bradykinin, leukotriene B4, prostaglandin E2, and substance P level in synovial fluid between successful and unsuccessful cases. J Oral Maxillofac Surg. 2007;65(2):242-7. since there is a positive correlation between the concentration of bradykinin and the synovitis degree2929 Nishimura M, Segami N, Kaneyama K, Suzuki T, Miyamaru M. Relationships between pain-related mediators and both synovitis and joint pain in patients with internal derangements and osteoarthritis of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94(3):328-32..

Eicosanoids

Eicosanoids are composites with great potency and a broad spectrum of biological activity, being originated by the oxygenation of long-chain polyunsaturated fatty acids1919 Oliveira Junior JO, Portella Junior CS, Cohen CP. Inflammatory mediators of neuropathic pain. Rev Dor. 2016;17(Suppl 1):35-42.. The arachidonic acid (AA), present in cell membranes, is the most abundant and important eicosanoid precursor2020 Yagiela JA, Dowd FJ, Johnson B, Mariotti A. Farmacologia e Terapêutica para Dentistas. 6ª ed. Mosby Elsevier; 2011. 318-52p.. AA is present in the membranes of the body cells. It is an essential fatty acid, of the Omega-6 family, formed by a 20-carbon chain with four double bonds (allowing several areas of the molecule to be oxidized)77 Brunton LL, Chabner BA, Knollman BA. As Bases Farmacológicas da Terapêutica de Goodman e Gilman. 12ª ed. McGraw Hill; 2012. 563-600p.. The cell stress resulting from the injury generates, as a consequence, an increase of calcium permeability with higher inflow to the interior of the cell, activating the action of the acyl-hydrolases enzymes (phospholipase A2 and C) that breaks up the phospholipids and promotes the generation of AA molecules available in the cytosol88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. AA is oxidized, mainly, by five enzymatic pathways (two cyclooxygenases and three lipoxygenases) producing eicosanoids (prostaglandins, thromboxanes, leukotrienes), that play a fundamental role in the inflammatory process2020 Yagiela JA, Dowd FJ, Johnson B, Mariotti A. Farmacologia e Terapêutica para Dentistas. 6ª ed. Mosby Elsevier; 2011. 318-52p..

Cyclooxygenase products

Cyclooxygenase (COX), enzymes present in the cytosol and bond to the endoplasmic reticulum of the cells, generate the synthesis of prostaglandins (PGE2, PGF2), prostacyclins (PGI2) and thromboxanes (TxA2)2020 Yagiela JA, Dowd FJ, Johnson B, Mariotti A. Farmacologia e Terapêutica para Dentistas. 6ª ed. Mosby Elsevier; 2011. 318-52p.. Prostaglandins and prostacyclins act as modulators of the exudative phenomena in late periods (after some hours of the onset of the inflammatory process) incrementing the histamine and kinins effect on the specific receptors, by increasing its sensitivity2424 Wannamacher L, Ferreira MBC. Farmacologia Clínica para Dentistas. 3ª ed. Guanabara Koogan; 2007. 129-43p.. Moreover, prostaglandins promote nerve endings hyperalgesia making them more sensitive to the action of pain mediators (histamine, serotonin, and kinins) which makes the local pain, induced by mechanical and chemical agents, stronger88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. PGE2 is present in high concentrations in the synovial fluid of TMJ involved in an inflammatory process, playing an important role in the development and maintenance of the inflammation3030 Alstergren P, Kopp S. Prostaglandin E2 in temporomandibular joint synovial fluid and its relation to pain and inflammatory disorders. J Oral Maxillofac Surg. 2000;58(2):180-6., such as the allodynia involved in these processes through the regulation of the 1.7 voltage-dependent sodium channels that have a modulating function in this type of pain3131 Zhang P, Gan YH. Prostaglandin E2 upregulated trigeminal ganglionic sodium channel 1.7 involving temporomandibular joint inflammatory pain in rats. Inflammation. 2017;40(3):1102-9.. The TxA2 is an important intravascular coagulant, being physiologically inhibited by PGI2(vasodilator). This constant opposition maintains the intravascular normality88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p..

Lipoxygenase products

In the leukocytes, part of the AA molecules is submitted to the action of lipoxygenases (5-, 12- and 15-LOX), resulting in the formation of leukotrienes (LT)77 Brunton LL, Chabner BA, Knollman BA. As Bases Farmacológicas da Terapêutica de Goodman e Gilman. 12ª ed. McGraw Hill; 2012. 563-600p.. Leukotrienes have a chemotactic function, aggregation, and degranulation of polymorphonuclears, as well as the stimulation of leukocytes adherence to the endothelial wall during the formation of the inflammatory infiltrate88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. High concentrations of leukotrienes (LTB4) are found in the synovial fluid of inflamed TMJ3232 Quinn JH, Bazan NG. Identification of prostaglandin E2 and leukotriene B4 in the synovial fluid of painful, dysfunctional temporomandibular joints. J Oral Maxillofac Surg. 1990;48(9):968-71., having a positive correlation between the degree of synovitis and the level of LTB42929 Nishimura M, Segami N, Kaneyama K, Suzuki T, Miyamaru M. Relationships between pain-related mediators and both synovitis and joint pain in patients with internal derangements and osteoarthritis of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94(3):328-32..

Platelet activating factor

As a response to specific stimuli (immune, tissue injuries), during the phosphorylation of phospholipids in phospholipase2, there is also the formation of the platelet activating factor (PAF) that is released by leukocytes, mast cells, and platelets88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. PAF induces the expression of adhesion molecule that recruits the inflammatory cells to the endothelium, in addition to contrib-gouputing to the inflammation exudative phenomena when produced by mast cells and leukocytes2424 Wannamacher L, Ferreira MBC. Farmacologia Clínica para Dentistas. 3ª ed. Guanabara Koogan; 2007. 129-43p.. High concentrations of PAF are found in inflammatory processes involving the TMJ3232 Quinn JH, Bazan NG. Identification of prostaglandin E2 and leukotriene B4 in the synovial fluid of painful, dysfunctional temporomandibular joints. J Oral Maxillofac Surg. 1990;48(9):968-71..

Nitric oxide

Nitric oxide (NO) is a free radical that is formed from the conversion of L-arginine and L-citrulline by nitric oxide enzymes synthetases, in endothelial cells in the CNS, the cardiac muscle, and macrophages2424 Wannamacher L, Ferreira MBC. Farmacologia Clínica para Dentistas. 3ª ed. Guanabara Koogan; 2007. 129-43p.. NO promotes muscle relaxation of blood vessels leading to vasodilation (a process that culminates in the formation of hyperemia and hyperthermia in inflammatory processes), besides reducing platelet aggregation88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. In the TMJ, NO is involved in painful conditions3333 Schütz TC, Andersen ML, Tufik S. Influence of temporomandibular joint pain on sleep patterns: role of nitric oxide. J Dent Res. 2004 ;83(9):693-7. as well as in the pathogenesis and the progression of internal disorders3434 Güven O, Tozoglu S, Tekin U, Salmanoglu B, Günes O. Relationship between activity of gluthatione peroxidase and nitric oxide in synovial fluid and the progression of temporomandibular joint internal derangement. J Craniofac Surg. 2015;26(3):e210-3..

Pro-inflammatory cytokines

The migration of cells to the region where the inflammation is occurring is also strongly influenced by the cytokines action3535 de Oliveira CM, Sakata RK, Issy AM, Gerola LR, Salomão R. [Cytokines and pain]. Rev Bras Anestesiol. 2011;61(2):255-65. English, Portuguese, Spanish.. These are peptides or polypeptides produced by the inflammatory or tissue cells, in conditions of normality, but also, especially, in cell mechanic, biochemical and/or functional cell stress as it is characterized in an area with an inflammatory process88 Consolaro A. Inflamação e Reparo. 2ª ed. Dental Press; 2015. 63-120p.. Besides stimulating the leukocyte cell adhesion to the vascular endothelium and inducing the synthesis and release of prostaglandins, the increase in the concentration of pro-inflammatory cytokines has been associated to the reabsorption of bone tissue in the TMJ3636 Kaneyama K, Segami N, Sun W, Sato J, Fujimura K. Levels of soluble cytokine factors in temporomandibular joint effusions seen on magnetic resonance images. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99(4):411-8.. Among the cytokines in the TMJ inflammation are the tumor necrosis factor (TNF-a) and the interleukins (especially IL-1 and IL-6)3737 Kellesarian SV, Al-Kheraif AA, Vohra F, Ghanem A, Malmstrom H, Romanos GE, et al. Cytokine profile in the synovial fluid of patients with temporomandibular joint disorders: a systematic review. Cytokine. 2016;77:98-106..

Tumor necrosis factor

TNF-a is a pro-inflammatory cytokine mainly produced by monocytes, macrophages, and T-linphocytes3535 de Oliveira CM, Sakata RK, Issy AM, Gerola LR, Salomão R. [Cytokines and pain]. Rev Bras Anestesiol. 2011;61(2):255-65. English, Portuguese, Spanish.. After traumas, surgical procedures or during infections, the TNF-a is one of the earliest and potent mediators of the inflammatory response. Its plasma half-life is only 20 minutes, enough to cause metabolic and hemodynamic important changes and to activate other cytokines3838 Curfs JH, Meis JF, Hoogkamp-Korstanje JA. A primer on cytokines: sources, receptors, effects, and inducers. Clin Microbiol Rev. 1997;10(4):742-80.. TNF-a acts activating coagulation, stimulating the expression or release of adhesion molecules, PGE2, PAF, glucocorticoids, eicosanoids and influencing cell apoptosis3939 Raeburn CD, Sheppard F, Barsness KA, Arya J, Harken AH. Cytokines for surgeons. Am J Surg. 2002;183(3):268-73.. This cytokine plays a key role in the development of TMD4040 Furquim BD, Flamengui LM, Repeke CE, Cavalla F, Garlet GP, Conti PC. Influence of TNF-a-308 G/A gene polymorphism on temporomandibular disorder. Am J Orthod Dentofacial Orthop. 2016;149(5):692-8.. Its increased expression promotes the beginning and progression of multiple inflammatory diseases, including the ones that involve the TMJ4141 Taylor PC, Williams RO, Feldmann M. Tumour necrosis factor alpha as a therapeutic target for immune-mediated inflammatory diseases. Curr Opin Biotechnol. 2004;15(6):557-63.. This fact is confirmed by results in which high TNF-a levels in the TMJ are positively correlated with acute and chronic joint inflammation, destruction of the connective tissue and pain in this joint4242 Fredriksson L, Alstergren P, Kopp S. Tumor necrosis factor-alpha in temporomandibular joint synovial fluid predicts treatment effects on pain by intra-articular glucocorticoid treatment. Mediators Inflamm. 2006;2006(6):59425.,4343 Ahmed N, Petersson A, Catrina AI, Mustafa H, Alstergren P. Tumor necrosis factor mediates temporomandibular joint bone tissue resorption in rheumatoid arthritis. Acta Odontol Scand. 2015;73(3):232-40..

Interleukin-1 (IL-1)

IL-1 is intensely produced by macrophages, monocytes, fibroblasts and dendritic cells, but it is also expressed by B lymphocytes, NK cells, and epithelial cells, and it is one of the most important markers of induction of the inflammatory response associated with acute infection4444 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.. The IL-1 system includes, at least, 21 different molecules represented by the IL-1 receptors, co-receptors, antagonists, and endogenous ligands. There are three types of ligands: IL-1a and IL-1b (both have an almost indistinguishable pro-inflammatory effect), and the IL-1 receptor antagonist (IL-1RA) that inhibits the pro-inflammatory functions acting as a competitive inhibitor of the receptor. There are also two different IL-1 receptors: the type 1 and type 2. The type 1 IL-1 receptor is responsible for the induction of intracellular signal transductions after binding with IL-1. The type 2 IL-1 receptor acts binding to IL-1 without producing any effect, thus reducing its general availability to bind and to initiate an inflammatory response4545 Tominaga K, Habu M, Sukedai M, Hirota Y, Takahashi T, Fukuda J. IL-1 beta, IL-1 receptor antagonist and soluble type II IL-1 receptor in synovial fluid of patients with temporomandibular disorders. Arch Oral Biol. 2004;49(6):493-9.. The intricate balance of molecules and receptors of the IL-1 family has a deep effect on the TMJ homeostasis. Many studies indicated that higher levels of IL-1a and IL-1b are present in the synovial fluid of patients with TMD4646 Sorenson A, Hresko K, Butcher S, Pierce S, Tramontina V, Leonardi R, et al. Expression of Interleukin-1 and temporomandibular disorder: contemporary review of the literature. Cranio. 2017;19:1-5. [Epub ahead of print]..

Interleukin-1 (IL-6)

IL-6 is a pleiotropic cytokine produced by some types of cells, such as synovial cells, monocytes, macrophages, and fibroblasts4747 Nishimoto N, Kishimoto T, Yoshizaki K. Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis. 2000;59 (Suppl 1):i21-7.. It regulates immune reactions, inflammation, hematopoiesis, and carcinogenesis4848 Gunson MJ, Arnett GW, Milam SB. Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. J Oral Maxillofac Surg. 2012;70(8):1918-34.,4949 Sato J, Segami N, Nishimura M, Demura N, Yoshimura H, Yoshitake Y, et al. Expression of interleukin 6 in synovial tissues in patients with internal derangement of the temporomandibular joint. Br J Oral Maxillofac Surg. 2003;41(2):95-101., and also mediates the induction of the differentiation process of the osteoclast progenitor and the osteoclastic activity5050 Fu K, Ma X, Zhang Z, Pang X, Chen W. Interleukin-6 in synovial fluid and HLADR expression in synovium from patients with temporomandibular disorders. J Orofac Pain. 1995;9(2):131-7.. When a tissue injury occurs, IL-6 plasma concentrations are detectable within 60 minutes, with a peak between 4 and 6 hours that can persist for up to 10 days. IL-6 promotes the maturation and activation of neutrophils, maturation of macrophages and the differentiation/maintenance of cytotoxic T-lymphocytes and natural killers cells5151 Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery, 2000;127(2):117-26.. Moreover, IL-6 is important for the transition of acute inflammation to chronic5252 Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 2003;24(1): 25-9.. The literature points IL-6 as one of the major pro-inflammatory cytokines that contrib-goupute to the pathogenesis of the TMJ inflammation and disorders4848 Gunson MJ, Arnett GW, Milam SB. Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. J Oral Maxillofac Surg. 2012;70(8):1918-34.,5353 Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th-1 cell-mediated murine colitis. J Immunol. 2000;164(9):4878-82.

54 Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, et al. Interleukin-6 is required for the development of collagen induced arthritis. J Exp Med. 1998;187(4):461-8.

55 Gunson MJ, Arnett GW, Milam SB. Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. J Oral Maxillofac Surg. 2012;70(8):1918-34.
-5656 De Alcântara Camejo F, Azevedo M, Ambros V, Caporal KST, Doetzer AD, Almeida LE, et al. Interleukin-6 expression in disc derangement of human temporomandibular joint and association with osteoarthrosis. J Craniomaxillofac Surg. 2017;45(5):768-74..

CONCLUSION

Understanding the inflammatory process, with the different mediators and mechanisms can contrib-goupute to better knowledge, making possible to select the best therapy to be used in the cases of temporomandibular arthralgias.

  • Sponsoring sources: none.

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    Furquim BD, Flamengui LM, Repeke CE, Cavalla F, Garlet GP, Conti PC. Influence of TNF-a-308 G/A gene polymorphism on temporomandibular disorder. Am J Orthod Dentofacial Orthop. 2016;149(5):692-8.
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    Fredriksson L, Alstergren P, Kopp S. Tumor necrosis factor-alpha in temporomandibular joint synovial fluid predicts treatment effects on pain by intra-articular glucocorticoid treatment. Mediators Inflamm. 2006;2006(6):59425.
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    Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.
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    Tominaga K, Habu M, Sukedai M, Hirota Y, Takahashi T, Fukuda J. IL-1 beta, IL-1 receptor antagonist and soluble type II IL-1 receptor in synovial fluid of patients with temporomandibular disorders. Arch Oral Biol. 2004;49(6):493-9.
  • 46
    Sorenson A, Hresko K, Butcher S, Pierce S, Tramontina V, Leonardi R, et al. Expression of Interleukin-1 and temporomandibular disorder: contemporary review of the literature. Cranio. 2017;19:1-5. [Epub ahead of print].
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    Gunson MJ, Arnett GW, Milam SB. Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. J Oral Maxillofac Surg. 2012;70(8):1918-34.
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    Sato J, Segami N, Nishimura M, Demura N, Yoshimura H, Yoshitake Y, et al. Expression of interleukin 6 in synovial tissues in patients with internal derangement of the temporomandibular joint. Br J Oral Maxillofac Surg. 2003;41(2):95-101.
  • 50
    Fu K, Ma X, Zhang Z, Pang X, Chen W. Interleukin-6 in synovial fluid and HLADR expression in synovium from patients with temporomandibular disorders. J Orofac Pain. 1995;9(2):131-7.
  • 51
    Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery, 2000;127(2):117-26.
  • 52
    Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 2003;24(1): 25-9.
  • 53
    Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th-1 cell-mediated murine colitis. J Immunol. 2000;164(9):4878-82.
  • 54
    Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, et al. Interleukin-6 is required for the development of collagen induced arthritis. J Exp Med. 1998;187(4):461-8.
  • 55
    Gunson MJ, Arnett GW, Milam SB. Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. J Oral Maxillofac Surg. 2012;70(8):1918-34.
  • 56
    De Alcântara Camejo F, Azevedo M, Ambros V, Caporal KST, Doetzer AD, Almeida LE, et al. Interleukin-6 expression in disc derangement of human temporomandibular joint and association with osteoarthrosis. J Craniomaxillofac Surg. 2017;45(5):768-74.

Publication Dates

  • Publication in this collection
    Jan-Mar 2018

History

  • Received
    01 Sept 2017
  • Accepted
    10 Jan 2018
Sociedade Brasileira para o Estudo da Dor Av. Conselheiro Rodrigues Alves, 937 Cj2 - Vila Mariana, CEP: 04014-012, São Paulo, SP - Brasil, Telefones: , (55) 11 5904-2881/3959 - São Paulo - SP - Brazil
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