Genetic Studies and Approaches on TMJ Pathologies

  • Didem Ozdemir-Ozenen
  • Derya Tabakcilar
  • Meltem Ozdemir-Karatas


TMJ diseases and their associated pain are common in the community. A large number of etiologic studies are being conducted to establish new therapies and to increase the protective approaches. Since environmental factors produce different responses in each individual, the genetic influence in TMJ pain has become the foreground. In this part of the book, genetic factors in TMJ development and diseases have been compiled.


Temporomandibular disorders Genetic factors Temporomandibular development Pain 


  1. 1.
    Oakley M, Vieira AR. The many faces of the genetics contribution to temporomandibular joint disorder. Orthod Craniofacial Res. 2008;11(3):125–35.CrossRefGoogle Scholar
  2. 2.
    Magnusson T, Egermark I, Carlsson GE. A prospective investigation over two decades on signs and symptoms of temporomandibular disorders and associated variables. A final summary. Acta Odontol Scand. 2005;63(2):99–109.CrossRefGoogle Scholar
  3. 3.
    De Leeuw R. Orofacial pain: guidelines for assessment, diagnosis, and management. In: Klasser GD, editor. Orofacial pain. 5th ed. Chicago: Quintessence Publishing Co; 2013. p. 129–204.Google Scholar
  4. 4.
    Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14(1):135–43.CrossRefGoogle Scholar
  5. 5.
    Shibata S, Suda N, Yoda S, Fukuoka H, Ohyama K, Yamashita Y, et al. Runx2-deficient mice lack mandibular condylar cartilage and have deformed Meckel?s cartilage. Anat Embryol. 2004;208(4):273–80.CrossRefGoogle Scholar
  6. 6.
    Hinton RJ. Genes that regulate morphogenesis and growth of the temporomandibular joint: a review. Dev Dyn. 2014;243(7):864–74.CrossRefGoogle Scholar
  7. 7.
    Shibata S, Suda N, Suzuki S, Fukuoka H, Yamashita Y. An in situ hybridization study of Runx2, Osterix, and Sox9 at the onset of condylar cartilage formation in fetal mouse mandible. J Anat. 2006;208(2):169–77.CrossRefGoogle Scholar
  8. 8.
    Fukuoka H, Shibata S, Suda N, Yamashita Y, Komori T. Bone morphogenetic protein rescues the lack of secondary cartilage in Runx2-deficient mice. J Anat. 2007;211(1):8–15.CrossRefGoogle Scholar
  9. 9.
    Mori-Akiyama Y, Akiyama H, Rowitch DH, de Crombrugghe B. Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest. Proc Natl Acad Sci. 2003;100(16):9360–5. Available from: Scholar
  10. 10.
    Wang Y, Liu C, Rohr J, Liu H, He F, Yu J, et al. Tissue interaction is required for glenoid fossa development during temporomandibular joint formation. Dev Dyn. 2011;240(11):2466–73.CrossRefGoogle Scholar
  11. 11.
    Purcell P, Jheon A, Vivero MP, Rahimi H, Joo A, Klein OD. Spry1 and Spry2 are essential for development of the temporomandibular joint. J Dent Res. 2012;91(4):387–93.CrossRefGoogle Scholar
  12. 12.
    Shibukawa Y, Young B, Wu C, Yamada S, Long F, Pacifici M, et al. Temporomandibular joint formation and condyle growth require Indian hedgehog signaling. Dev Dyn. 2007;236(2):426–34.CrossRefGoogle Scholar
  13. 13.
    Purcell P, Joo BW, Hu JK, et al. Temporomandibular joint formation requires two distinct hedgehogdependent steps. Proc Natl Acad Sci. 2010;107(8):18297–302.Google Scholar
  14. 14.
    Koyama E, Ochiai T, Rountree RB, Kingsley DM, Enomoto-Iwamoto M, Iwamoto M, et al. Synovial joint formation during mouse limb skeletogenesis: roles of Indian hedgehog signaling. Ann N Y Acad Sci. 2007;1116:100–12.CrossRefGoogle Scholar
  15. 15.
    Michikami I, Fukushi T, Honma S, Yoshioka S, Itoh S, Muragaki Y, et al. Trps1 is necessary for normal temporomandibular joint development. Cell Tissue Res. 2012;348(1):131–40.CrossRefGoogle Scholar
  16. 16.
    Napierala D, Sam K, Morello R, Zheng Q, Munivez E, Shivdasani RA, et al. Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome. Hum Mol Genet. 2008;17(14):2244–54.CrossRefGoogle Scholar
  17. 17.
    Gu S, Wei N, Yu L, Fei J, Chen YP. Shox2-deficiency leads to dysplasia and ankylosis of the temporomandibular joint in mice. Mech Dev. 2008;125(8):729–42.CrossRefGoogle Scholar
  18. 18.
    Raphael KG, Marbach JJ, Gallagher RM, Dohrenwend BP. Myofascial TMD does not run in families. Pain. 1999;80(1–2):15–22.CrossRefGoogle Scholar
  19. 19.
    Heiberg A, Helöe B, Heiberg AN, Helöe LA, Magnus P, Berg K, et al. Myofascial pain dysfunction (MPD) syndrome in twins. Community Dent Oral Epidemiol. 1980;8(8):434–6.CrossRefGoogle Scholar
  20. 20.
    Michalowicz BS, Pihlstrom BL, Hodges J, Bouchard TJ Jr. No heritability of temporomandibular joint signs and symptoms. J Dent Res. 2000;79:1573–8.CrossRefGoogle Scholar
  21. 21.
    Visscher CM, Lobbezoo F. TMD pain is partly heritable. A systematic review of family studies and genetic association studies. J Oral Rehabil. 2015;42(5):386–99.CrossRefGoogle Scholar
  22. 22.
    Smith SB, Maixner DW, Greenspan JD, Dubner R, Fillingim RB, Ohrbach R, et al. Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J Pain. 2011;12(11 SUPPL):T92–101.CrossRefGoogle Scholar
  23. 23.
    Meloto CB, Serrano PO, Ribeiro-Dasilva MC, Rizzatti-Barbosa CM. Genomics and the new perspectives for temporomandibular disorders. Arch Oral Biol. 2011;56(11):1181–91.CrossRefGoogle Scholar
  24. 24.
    Smith SB, Mir E, Bair E, Slade GD, Dubner R, Fillingim RB, et al. Genetic variants associated with development of TMD and its intermediate phenotypes: the genetic architecture of TMD in the OPPERA prospective cohort study. J Pain. 2013;14(12 Suppl):T91–T101.e3.CrossRefGoogle Scholar
  25. 25.
    Kim BS, Kim YK, Yun PY, Lee E, Bae J. The effects of estrogen receptor α polymorphism on the prevalence of symptomatic temporomandibular disorders. J Oral Maxillofac Surg. 2010;68(12):2975–9.CrossRefGoogle Scholar
  26. 26.
    Leresche L. Epidemiology of temporomandibular disorders: implications for the investigation. Crit Rev Oral Biol Med. 1997;8(3):291–305.CrossRefGoogle Scholar
  27. 27.
    LeResche L, Mancl L, Sherman JJ, Gandara B, Dworkin SF. Changes in temporomandibular pain and other symptoms across the menstrual cycle. Pain. 2003;106(3):253–61.CrossRefGoogle Scholar
  28. 28.
    Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J, Worthington HV. Association between female hormonal factors and oro-facial pain: study in the community. Pain. 2002;97(1–2):5–10.CrossRefGoogle Scholar
  29. 29.
    Landi N, Lombardi I, Manfredini D, Casarosa E, Biondi K, Gabbanini M, et al. Sexual hormone serum levels and temporomandibular disorders. A preliminary study. Gynecol Endocrinol. 2005;20(2):99–103.CrossRefGoogle Scholar
  30. 30.
    Omar Abubaker A, Raslan WF, Sotereanos GC. Estrogen and progesterone receptors in temporomandibular joint discs of symptomatic and asymptomatic persons: A preliminary study. J Oral Maxillofac Surg. 1993;51(10):1096–100.CrossRefGoogle Scholar
  31. 31.
    Ribeiro-Dasilva MC, Peres Line SR, Leme Godoy dos Santos MC, Arthuri MT, Hou W, Fillingim RB, et al. Estrogen receptor-α polymorphisms and predisposition to TMJ disorder. J Pain. 2009;10(5):527–33.CrossRefGoogle Scholar
  32. 32.
    Kang SC, Lee DG, Choi JH, Kim ST, Kim YK, Ahn HJ. Association between estrogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients. Int J Oral Maxillofac Surg. 2007;36(5):391–4.CrossRefGoogle Scholar
  33. 33.
    Hranilovic D, Stefulj J, Schwab S, Borrmann-hassenbach M, Albus M, Jernej B, et al. Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry. 2004;55:1090–4.CrossRefGoogle Scholar
  34. 34.
    Herken H, Erdal E, Mutlu N, Barlas Ö, Cataloluk O, Oz F, et al. Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. Am J Orthod Dentofac Orthop. 2001;120(3):308–13.CrossRefGoogle Scholar
  35. 35.
    Ojima K, Watanabe N, Narita N, Narita M. Temporomandibular disorder is associated with a serotonin transporter gene polymorphism in the Japanese population. BioPsychoSoc Med. 2007;1:1–4.CrossRefGoogle Scholar
  36. 36.
    Melis M, Di Giosia M. The role of genetic factors in the etiology of temporomandibular disorders: a review. Cranio. 2016;34(1):43–51.CrossRefGoogle Scholar
  37. 37.
    Mutlu N, Erdal M, Herken H, Oz G, Bayazıt Y. T102C polymorphism of the 5-HT2A receptor gene may be associated with temporomandibular dysfunction. Oral Dis. 2004;10(6):349–52.CrossRefGoogle Scholar
  38. 38.
    De Freitas LVS, Lopes ACP, Piatto VB, Maniglia JV. Association of temporomandibular dysfunction with the 102T-C polymorphism in the serotonin receptor gene in Brazilian patients. Arch Med Sci. 2013;9(6):1013–8.CrossRefGoogle Scholar
  39. 39.
    Slade GD, Smith SB, Zaykin DV, Tchivileva IE, Gibson DG, Yuryev A, et al. Facial pain with localized and widespread manifestations: separate pathways of vulnerability. Pain. 2013;154(11):2335–43.CrossRefGoogle Scholar
  40. 40.
    Etoz OA, Ataoglu H, Erdal ME. Association between tryptophan hydroxylase gene polymorphism and painful non- osseous temporomandibular disorders. Saudi Med J. 2008;29(9):1352–4.PubMedGoogle Scholar
  41. 41.
    Kopp S. Neuroendocrine, immune, and local responses related to temporomandibular disorders. J Orofac Pain. 2001;15:9–28.PubMedGoogle Scholar
  42. 42.
    Kopp S. The influence of neuropeptides, serotonin, and interleukin 1beta on temporomandibular joint pain and inflammation. J Oral Maxillofac Surg. 1998;56(2):189–91.CrossRefGoogle Scholar
  43. 43.
    Männistö PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev. 1999;51(4):593–628.PubMedGoogle Scholar
  44. 44.
    Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both β2- and β3-adrenergic receptors. Pain. 2007;128(3):199–208.CrossRefGoogle Scholar
  45. 45.
    Diatchenko L, Anderson AD, Slade GD, Fillingim RB, Shabalina SA, Higgins TJ, et al. Three major haplotypes of the β2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder. Am J Med Genet B Neuropsychiatr Genet. 2006;141(5):449–62.CrossRefGoogle Scholar
  46. 46.
    Michelotti A, Liguori R, Toriello M, Sacchetti L, et al. Clin J Pain. 2014;30(2):129–33.PubMedGoogle Scholar
  47. 47.
    Slade GD, Diatchenko L, Bhalang K, Sigurdsson A, Fillingim RB, Belfer I, et al. Influence of psychological factors on risk of temporomandibular disorders. J Dent Res. 2007;86(11):1120–5.CrossRefGoogle Scholar
  48. 48.
    Aneiros-Guerrero A, Lendinez AM, Palomares AR, Perez-Nevot B, Aguado L, Mayor-Olea A, et al. Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder. BMC Med Genet. 2011;12:1–9.CrossRefGoogle Scholar
  49. 49.
    Yamaza T, Masuda KF, Atsuta I, Nishijima N, Kido MA, Tanaka T. Oxidative stress-induced DNA damage in the synovial cells of the Temporomandibular joint in the rat. J Dent Res. 2004;83(8):619–24.CrossRefGoogle Scholar
  50. 50.
    Ueno T, Yamada M, Sugita Y, Ogawa T. N-acetyl cysteine protects TMJ chondrocytes from oxidative stress. J Dent Res. 2011;90(3):353–9.CrossRefGoogle Scholar
  51. 51.
    Huang B, Takahashi K, Sakata T, Kiso H, Sugai M, Fujimura K, et al. Increased risk of temporomandibular joint closed lock: a case-control study of ANKH polymorphisms. PLoS One. 2011;6(10):2–8.Google Scholar
  52. 52.
    Lark MW, Bayne EK, Flanagan J, Harper CF, Hoerrner LA, Hutchinson NI, et al. Aggrecan degradation in human cartilage: evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Investig. 1997;100(1):93–106.CrossRefGoogle Scholar
  53. 53.
    Planello AC, Campos MIG, Meloto CB, Secolin R, Rizatti-Barbosa CM, Line SRP, et al. Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration. Eur J Oral Sci. 2011;119(1):1–6.CrossRefGoogle Scholar
  54. 54.
    Yoshida K, Takatsuka S, Tanaka A, Hatada E, Nakamura H, Nakagawa K, et al. Aggrecanase analysis of synovial fluid of temporomandibular joint disorders. Oral Dis. 2005;11(5):299–302.CrossRefGoogle Scholar
  55. 55.
    Yoshida K, Takatsuka S, Hatada E, Nakamura H, Tanaka A, Ueki K, et al. Expression of matrix metalloproteinases and aggrecanase in the synovial fluids of patients with symptomatic temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(1):22–7.CrossRefGoogle Scholar
  56. 56.
    Duff GW. Cytokines and acute phase proteins in rheumatoid arthritis. Stand J Rheumatol. 1994;100(9):20.Google Scholar
  57. 57.
    Slade GD, Conrad MS, Diatchenko L, Rashid NU, Zhong S, Smith S, et al. Cytokine biomarkers and chronic pain: association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness. Pain. 2011;152(12):2802–12.CrossRefGoogle Scholar
  58. 58.
    OMIM (Online Mendelian Inheritance in Man®):An Online Catalog of Human Genes and Genetic Disorders [Internet]. [cited 2018 Apr 1]. Available from:

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Didem Ozdemir-Ozenen
    • 1
  • Derya Tabakcilar
    • 1
  • Meltem Ozdemir-Karatas
    • 2
  1. 1.Yeditepe University, Faculty of Dentistry, Department of Pediatric DentistryIstanbulTurkey
  2. 2.Istanbul University, Faculty of Dentistry, Department of Maxillofacial ProsthodonticsIstanbulTurkey

Personalised recommendations