Estalo doloroso na ATM: o que a genética pode ajudar a explicar

Painful Temporomandibular J oint Clicking: A Genetic Point of View

Rodrigo Lorenzi Poluha, DDS , MSc , Aims: To determine whether there is an association between gene polymor- PhD phisms and patients with painful temporomandibular joint (TMJ) clicking when State Universit y of Maringá compared to patients with painless TMJ clicking and a healthy control group. Depar tment of Dentistr y Methods: In this pilot study, the genotypic and allelic frequencies of candi- Paraná , Brazil date single-nucleotide polymorphisms (SNP) were compared among 60 in - Flávia Fonseca Carvalho Soares, dividuals divided equally into three groups: patients with painful TMJ clicking DDS , MSc , PhD (n = 20); patients with painless TMJ clicking (n = 20); and healthy controls (n = F TC University Center 20). Par ticipants were genotyped for the following SNPs using real-time poly- Depar tment of Dentistr y merase chain reaction: MMP1 –16 0 71G / 2 G , COMT Va l15 8 M e t , TNF α –308, Vitória da Conquista Bahia , Bra zil I L1β +3954, I L6 –174, and I L1 0 –1082. The pressure pain threshold (PPT) Bruno D’Aurea Furquim, DDS , MSc , of the TMJ was also assessed. All variables were compared among groups. PhD Results: Patients with painful TMJ clicking had a significant association and Bauru Orofacial Pain Group a higher frequency of MMP1 –16 0 71G / 2 G (P = .042), COMT Va l15 8 M e t Depar tment of Prosthodontics (P = .030), and TNF α –308 ( P = .016) when compared to the other groups, as Bauru School of Dentistr y well as a lower frequency of I L1 0 –1082. Considering PPT values, a progres - Universit y of São Paulo sively lower mean was found in individuals with painful TMJ clicking, followed São Paulo, Brazil sequentially by the painless TMJ clicking and the control groups. Conclusion: Giancarlo De la Torre Canales, DDS , This pilot study showed that patients with painful TMJ clicking had a significant MSc , PhD association with mutant genot ypes related to degradation of extracellular matrix Interdisciplinar Investigation Center Egas components, pain, proinflammation, and anti-inflammation. Furthermore, these Moniz University Institute Egas Moniz patients also had significantly lower TMJ PPT values in all comparisons. J Oral Caparica, Portugal Facial Pain Headache 2022;36:229–235. doi: 10.11607/ofph.3115 Lívia Maria Sales Pinto Fiamengui, DDS , MSc , PhD Key words: genetic polymorphism, pain, temporomandibular joint, Depar tment of Restorative Dentistr y temporomandibular joint disc Federal Universit y of Ceará For taleza , Ceará , Brazil emporomandibular joint (TMJ) clicking is usually related to in - Leonardo Rigoldi Bonjardim, DDS , ternal derangements, such as disc displacement with reduction MSc , PhD T(DDWR), which is a sound produced when the condyle impacts Bauru Orofacial Pain Group, Depar tment against the disc when the disc is moved and repositioned through man- of Biological Sciences, Bauru School of Dentistr y, Universit y of São Paulo dibular movements.1– 3 TMJ clicking accounts for 30.7% of the clinical São Paulo, Brazil signs of temporomandibular disorders (TMDs) and is one of the most Paulo César Rodrigues Conti, DDS , common complaints in patients. 2,4 Although TMJ clicking is typically MSc , PhD painless, in some cases, DDWR is accompanied by TMJ pain that oc- Bauru Orofacial Pain Group curs or is intensified at the clicking moment, which is called painful TMJ Depar tment of Prosthodontics clicking.5 Some hypotheses have been raised to explain why this phe- Bauru School of Dentistr y nomenon happens, such as compression of the bilaminar zone and TMJ Universit y of São Paulo inflammation such as arthralgia. 6 São Paulo, Brazil Correspondence to: Several studies have investigated which clinical factors are impor t- Dr Rodrigo Lorenzi Poluha ant in patients with painful TMJ clicking, showing that the presence State Universit y of Maringá , Depar tment of awake bruxism and specific oral behaviors that create pressure on of Dentistr y the jaw, a somatosensory profile that is more sensitive to mechanical Mandacaru Avenue, 1550 pain tests, a less efficient pain modulation system, poor sleep qual - 87080-000, Maringá, Paraná, Brazil ity, and higher levels of hypervigilance, pain catastrophizing, and Email: rodrigopoluha@gmail.com kinesiophobia are key factors in these patients.5 –7 These data confirm

Submit ted September 20, 2021; the complex and multifactorial nature of TMJ clicking and pain, indicat- accepted June 4, 2022. ing that investigations including factors other than clinical should also ©2022 by Quintessence Publishing Co Inc be per formed. 8 Dynamic and somatosensory TMJ profiles are also regulated by genetic aspects.9 Some genetic association studies have investigated

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whether genetic polymorphisms are involved [n = 3]). Thus, the sample size was calculated to be in TMJ clicking and pain.10 Their findings indi - 60 individuals, homogenous as to race and social cate that individual genetic background plays a status, equally divided into three groups: role, contributing to the course and outcome of TMJ clicking and pain individually. 9 ,10 A single- • Group 1 was composed of 20 patients (18 nucleotide polymorphism (SNP) in specific genes women, 2 men, mean age of 33.50 ± 10.33 related to the degradation of extracellular matrix years) with unilateral painful TMJ clicking (DDWR components (such as matrix metallopeptidase 1 plus ar thralgia in the same TMJ). The mean pain [ M M P 1] ) ,11 pain sensitivity (such as catechol-O- intensity measured during the first appointment methyltransferase [COMT]),12 proinflammation (such with a 0 to 10 visual analog scale was 7.01 as tumor necrosis factor alpha [TNF α ], interleukin ± 1.09; however, no minimum intensity was 1 beta [IL1β ], and interleukin 6 [IL6])13 –15 and anti- established as an inclusion criterion. The patients inflammation (such as interleukin 10 [IL10])16 have al- in this group repor ted having complaints about ready been associated with several internal derange - TMJ clicking/pain for an average range of 15.20 ments of the TMJ. However, no previous study has ± 6.53 months. investigated the genes and genetic polymorphisms • Group 2 was composed of 20 patients (20 involved in patients with painful TMJ clicking. women, mean age of 32.50 ± 12.81 years) with Therefore, the present study aimed to determine unilateral painless TMJ clicking (DDWR only). whether there is an association between gene poly - There was no repor t or complaint of any previous morphisms and painful TMJ clicking when compared significant TMJ pain. The patients in this group to painless TMJ clicking and healthy control groups. repor ted having complaints about TMJ clicking The null hypothesis was that there would be no dif fer- for 22.28 ± 8.64 months. ence among these patient groups. • Group 3 (control group) was composed of 20 asymptomatic individuals (17 women, 3 men, mean age of 34.15 ± 11.60 years) with no TMJ Materials and Methods clicking and no arthralgia.

This pilot cross-sectional case-control study was Individuals were excluded due to pain other than conducted following the Helsinki Declaration and the arthralgia, TMJ sounds other than clicking (ie, crepi- recommendations of the Strengthening the Repor ting tation or terminal thud due to TMJ hypertranslation), of Obser vational Studies in Epidemiology (STROBE) having had previous surgical intervention in the TMJ, guidelines.17 The present study was approved by the or having systemic conditions such as fibromyalgia or Research Ethics Committee of the Bauru School of any degenerative joint disease. Dentistr y, University of São Paulo, Bauru, São Paulo, Bra zil (protocol 118/2010). DNA Collection and SNP Analysis The sample formation strategy was not random- DNA was ex tracted from each par ticipant’s saliva ized. The sample was obtained from 214 Brazilian using a QIAamp DNA Mini Kit (Qiagen) following individuals over 18 years of age who consecutive - the manufacturer’s instructions. DNA integrity was ly presented to the Bauru School of Dentistr y from checked as previously described. 13 For this inves - September 2012 to September 2013 requesting tigation, SNPs of specific genes already reported regular dental treatment (control group) or pre - in the literature to be related to several internal senting with complaints of clicking and/or pain derangements of the TMJ were selected. 11 –1 6 in the TMJ area. Recruitment of individuals was Allelic discrimination of variants COMT Va l15 8 M e t done through several advertisements placed on (r s 4 6 8 0), MMP1 –16071G/2G (rs1799750), the university campus and in city locations, posts TNF α –308 (rs1800629), I L1 0 –1082G>A on social media, and radio ads. Participants were (rs1800896), I L1β +3954 (rs1143634), and I L6 allocated to one of the groups according to clini - –174 (rs1800795) were performed in 3-mL re - cal examination based on the Research Diagnostic actions using TaqMan (Applied Biosystems) Criteria for Temporomandibular Disorders (RDC/ chemistry, as previously described. 10 Real-time TMD) Axis 1.18 The sample formation and study polymerase chain reaction (RT-PCR) was per - design were based on a previous investigation. 8 formed utilizing a 10-ng sample of DNA , ×1 con - G*Power software, version 3.1.9.2, was used for centration TaqMan SNP genotyping assays, ×1 sample size calculation. The following parameters concentration TaqMan Universal MasterMix, and were considered: test power of 0.8; significance H 20 q.s. 5 µL. The RT-PCR cycle conditions level of .05; and ef fect size of 0.4 for analysis of vari - were 60ºC for 30 seconds, 95ºC for 10 seconds, ance (ANOVA) with one intersubject factor (group 40 cycles at 92ºC for 15 seconds, 60ºC for 60

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Table 1 Comparison of Gene Polymorphisms Among Groups (n = 20 each) Painful TMJ clicking Painless TMJ clicking Control group P value

MMP1 –1 6 0 7 P r e s e n t (1G1G) 16 (8 0) A 12 (60) B 8 (40) C .042*Absent (2G2G) 4 (20) A 8 (40) B 12 (60) C

COMT Va l15 8 M e t Present (GG , AG) 15 (75) A 13 (55) B 6 (30) C .030*Absent (A A) 5 (25) A 7 (45) B 14 (70) C

TNF α–308 Present (GG , GA) 12 (60) A 6 (30) B 3 (15) B . 016 *Absent (A A) 8 (40) A 14 (70) B 17 (85) B

I L10 –1 0 8 2 Present (CC, CA) 5 (25) A 9 (45) B 13 (65) B .049*Absent (A A) 15 (75) A 11 (55) B 7 (35) B

I L6 –174 Present (GG , GC) 12 (60) A 7 (35) A 7 (35) A . 2 24Absent (CC) 8 (40) A 13 (65) A 13 (65) A

I L1 β+3954 Present (CC) 7 (35) A 7 (35) A 5 (25) A .829A b se nt (C T ) 13 (65) A 13 (65) A 15 (75) A

Data are repor ted as n (%) unless other wise indicated. *Statistically significant dif ference according to chi-square test . Dif ferent superscript capital let ters represent significant differences among groups.

seconds, and 60ºC for 30 seconds. 13 For reaction Result s quality control, a sample of the known genotype (positive control) and a no-DNA template sample Genotypes for all studied SNPs were in the Hardy- (negative control) were included in the plate, 13 Weinberg equilibrium. In the comparison of the SNP and only genotypes with an automatic call rate prevalence among groups, patients with painful > 95% were considered. Genotyping was per - TMJ clicking had a significantly higher frequency of formed blinded to group status. 13 MMP1 –16 0 7 1G / 2 G , COMT Val158Met, and TNF α –308 and a lower frequency of I L1 0 –10 8 2 G>A Pressure Pain Threshold of the TMJ when compared to the other groups (P .05). SNPs The PPT was determined as the arithmetic mean I L1β +3954 and I L6 –174 presented no dif ference in of three measurements (with a 10-minute inter - any comparisons (Table 1). val between them). Tests were performed on the Considering PP T values of the TMJ, significantly skin overlying the TMJ. In patients, the side of the lower values (1.11 ± 0.39) were found in patients with complaint was selected as the test side. In healthy painful TMJ clicking when compared to patients with controls, the dominant side was chosen as the test painless TMJ clicking (1.55 ± 0.45). The painless side. 5 ,19 TMJ clicking group also showed lower mean PP T val- ues than the control group (2.05 ± 0.67; Table 2). Statistical Analysis Normal distribution of the data was assessed us- ing Kolmogorov-Smirnov test. Chi-square test was Discussion used to assess deviations from the Hardy-Weinberg equilibrium and to compare the polymorphism prev - To the best of the authors’ knowledge, this is the first alence among groups. Pearson chi-square test was pilot study to describe patients with painful TMJ click - per formed for analysis of genotypes using the dom- ing from a genetic point of view. The results showed inant model. One-way analysis of variance (ANOVA) that these patients had a significant association and followed by post hoc Tukey test was used to compare a higher prevalence of mutant genotypes related to the PPT values of the TMJ. A 5% significance level degradation of ex tracellular matrix components, pain, was used for all tests. SPSS software version 25.0 and proinflammation (MMP1 r s179 975 0 , COMT (IBM) was used to analyze the data . rs4680, and TNF α rs1800629, respectively), as well

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Table 2 Comparison of PPT Among Groups Group comparison Dif ference in means (kgf/cm2) P value Group 1 x Group 2 0.44 . 0 24* Group 1 x Group 3 0.94 < . 0 01* Group 2 x Group 3 0.50 . 0 11 * *Statistically significant dif ference according to one-way ANOVA with Tukey post hoc test . Group 1 = painful TMJ clicking; Group 2 = painless TMJ click- ing; Group 3 = control group.

as a lower frequency of anti-inflammation gene poly- to the control group also makes sense, since COMT morphisms (I L1 0 rs1800896). Furthermore, these SNPs are described in the literature as involved in patients also showed significantly lower TMJ PP T val- several TMD disorders, even when the pain is not the ues when compared to the other groups. Thus, the main characteristic.12 Also, a TMJ with DDWR can null hypothesis was rejected. present some level of sensitization regardless of the In the present study, a significant association presence of significant clinical pain, 5 which can be with and a higher prevalence of the mutant geno - influenced by SNP rs4680. type MMP1 –16071G/2G was found in the painful Both SNPs related to proinflammation (TNF α TMJ clicking group when compared to the other –308) and anti-inflammation ( I L6 –174) were signifi - groups (Table 1). These results were expected due cantly associated with the painful TMJ clicking group, to several factors. First, it is already known that the as these polymorphisms showed, respectively, higher MMP1 –1607 polymorphism induces a higher local and lower prevalence in these patients when com- concentration of MMP1 , which contributes to quick - pared to the other groups. However, there was no dif- er degradation of the extracellular matrix of articu - ference when these SNPs were compared between lar tissues. 20, 21 With this gene polymorphism, the patients with painless TMJ clicking and the control physiologic balance of matrix metalloproteinases group individuals (Table 1). These results are in line and their inhibitors in the articular disc is disrupt - with the condition characteristics. Although the pres - ed, which can create an environment susceptible to ent study did not evaluate the TMJ synovial fluid to intra-articular disorders such as painful TMJ click - confirm the presence of inflammatory mediators, it ing.22–25 Second, it is interesting to note that, in the has been demonstrated in the literature that clinical present study, this polymorphism was also more TMJ arthralgia is mediated by inflammatory media - prevalent in the painless TMJ group when compared tors, and that in painful TMJ clicking due to arthral- to the control group. Although this finding is in ac - gia, the pain is related to TMJ inflammation.4–6 Also, cordance with previous literature that has already it is known that TNF α –308 polymorphism induces investigated and found an association between a higher production of TNF α (a proinflammatory cy - MMP1 SNP rs1799750 and simple DDWR,11,26,27 tokine present in a TMJ with inflammatory process- the present results indicate an important genetic e s) ,16,31–34 and that the I L1 0 –1082 polymorphism role of MMP1 in cases of worse prognosis of disc is associated with high production of I L1 0 (an anti- displacement, such as when accompanied by ar - inflammatory cytokine). 35,36 Therefore, the combina - thralgia. Future longitudinal studies should investi - tion of a higher frequency of proinflammation SNPs gate whether people with painful TMJ clicking and and a lower frequency of anti-inflammation SNPs MMP1 SNP can evolve to degenerative disorders is expected in an arthralgia scenario, such as pain- of the TMJ, since an association between these two ful TMJ clicking. These findings agree with previous variables has already been reported. 28 studies in which an association between these poly- A similar result was found in the COMT SNP morphisms and TMD was reported.10 ,13 ,16 However, analysis. In the present study, there was a signif - the present study is the only one so far to subdivide icant association and a higher prevalence of the the TMD sample into groups according to diagnosis mutant genotype COMT Val158Met in the painful and clinical characteristics. This methodology al - TMJ clicking group compared to the other groups lowed for better understanding of the pathophysiol- (Table 1). This was also an expected result, since it ogy of these conditions individually and not just in a is well known that COMT polymorphisms, especially large, heterogenous group of TMD patients. Val158Met, are strongly associated with increased For patients with altered TMJ mechanisms caused pain sensitivity once the SNP causes an amino acid by disc displacement and inflammation that can also substitution in the enzymatic polypeptide chain, re - sensitize the TMJ area 3 7, 3 8 and with a higher preva- sulting in lower thermostability and consequently less lence of mutant genotypes related to degradation COMT activity.29,30 The higher prevalence of COMT of extracellular matrix components, pain, and proin- Val158 Met in the painless TM J group when compared flammation, as well as a lower frequency of protective

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anti-inflammation gene polymorphisms, some level absence of synovial fluid analysis, gender compari - of somatosensorial sensitization in proportion to the son, the menstrual status of the female par ticipants, prevalence of the SNPs is expected to be found. This ethnicity, and psychosocial profiles, which are fac - could explain the PPT results found in the present tors that might influence pain sensitivity indepen- study. Patients with painful TMJ clicking presented dent of genetics. lower PPT values when compared to patients with painless TMJ clicking, and patients with painless TMJ clicking showed lower PP T means compared to the Conclusions control group (Table 2). This sequentially lower PP T is in agreement with previous studies, suggesting that In view of the results and limitations of this pilot there is a cer tain degree of sensitization in individuals study, it can be concluded that patients with pain - with DDWR with a cer tain degree of modification in ful TMJ clicking had a significant association and a response to the pressure applied. 5 higher prevalence of mutant genotypes related to It is also important to consider the female pre - degradation of ex tracellular matrix components, pain, dominance in this study. The female to male ratio in and proinflammation, and a lower frequency of anti- the present sample was 11:1. Although this gender inflammation gene polymorphisms. Also, these pa - distribution is higher than in previous studies (1.9:1 to tients had a higher TMJ pain sensitivity when com - 3 . 5 : 1) , 5,6 it is not surprising, as women tend to seek pared to the other groups. TMD treatment more often than men. In addition, the literature has already showed that TMJ disc dis- placement and ar thralgia are more prevalent in wom- Key Findings/Clinical Implications en.2,4 The greater occurrence of these pathologies in women could result from the influence of some Painful TMJ clicking is linked to a higher frequency of female-specific characteristics, such as a small - mutant genotypes related to degradation of the ex tra- er articular space, greater intra-articular pressure, cellular matrix, pain, and proinflammation, as well as a greater joint laxity, and higher TMJ pain levels pos - lower frequency of anti-inflammation polymorphisms. sibly caused by the influence of estrogen, which can The present results help explain the role of genetics increase inflammatory hyperalgesia in the TMJ area in cases of worse prognosis of disc displacement, and present a peripheral/central action in the mod- such as when accompanied by arthralgia. It is im- ulation of pain. 39,40 Besides that, other TMJ genetic por tant to consider a genetic study to elaborate the studies have also shown a higher prevalence of mu- treatment plan in painful clicking cases. tated genotypes related to tissue degradation, pain, and inflammation (such as MMP1 , COMT, TNF α , and I L1 0) in women.10 –13 , 41 Future gender comparison Acknowledgment s studies should help clarify the role of the gender- genetic relationship in TMJ conditions. This study was financed in part by the São Paulo Research This pilot study reveals interesting genetic in - Foundation (FAPESP), Brasil, and the Coordenação de sights about the phenomena of painful TMJ click - Aper feiçoamento de Pessoal de Nível Superior, Brasil (CAPES), ing. Both results—the presence and the absence Finance Code 001. of specific gene polymorphisms related to deg - The authors report no conflicts of interest. Author contributions: radation of extracellular matrix components, pain, R .L .P.: study conceptualization and design, data collection, data proinflammation, and anti-inflammation—can help analysis, manuscript preparation; F.F.C.S.: study conceptualiza - explain the occurrence of pain in only some cases tion and design, data analysis, manuscript preparation; B.D.A.F: data collection, clinical examinations, manuscript preparation; of TMJ clicking. These data reveal the importance G.D.T.C.: data collection, data analysis, manuscript preparation; of under taking a genetic study to elaborate a mech - L.M.S.P.F.: data collection, clinical examinations, manuscript anism-based, personalized treatment plan once a preparation; L.R.B.: subcoordinator, study conceptualization, re - genetic role has been identified in cases of worse vision of manuscript; P.C.R.C.: coordinator, study conceptualiza - prognosis of disc displacement, such as when ac - tion and design, data analysis, revision of manuscript. companied by arthralgia. Nevertheless, caution is important when judging the present findings. The small sample of this pilot study prevents ex trapolat - References ing the observed results beyond other populations different from the present one. Genome-wide as - 1. Poluha RL, Grossmann E, Iwaki LCV, Uchimura T T, Santana sociation studies (GWAS) with larger samples are RG, Iwaki Filho L. Myofascial trigger points in patients with encouraged in the future. Additionally, the pres - temporomandibular joint disc displacement with reduction: A cross-sectional study. J Appl Oral Sci 2018;26:e20170578. ent investigation has other limitations, such as the

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