Molecular Changes Involving MEK3-p38 MAPK Activation in Chronic Masticatory Myalgia

J Dent Res. 2016 Sep;95(10):1169-75. doi: 10.1177/0022034516659441. Epub 2016 Jul 14.


The exact mechanism underlying chronic masticatory myalgia (CMM), a conspicuous symptom in temporomandibular disorders, remains unclear. This investigation compared gene expression profiles between CMM patients and healthy subjects. Peripheral blood leukocytes were collected in 8 cases and 8 controls and subjected to whole genome microarray analyses. Data were analyzed with Gene Ontology and interactive pathways analyses. According to Gene Ontology analysis, categories such as ion transport, response to stimuli, and metabolic process were upregulated. The pathway analysis suggested overexpression of the mitogen-activated protein kinase (MAPK) pathway in CMM patients and to a higher degree in a pathway network. Overexpression of representative members of the MAPK pathway-including MAPK kinase 3 (MEK3), calcium voltage-gated channel auxiliary subunit gamma 2 (CACNG2), and growth arrest and DNA damage-inducible gamma (GADD45G)-was validated with real-time polymerase chain reaction. The upregulation of MEK3 was negatively correlated with the age of the CMM group. In the next step, the authors focused on MEK3, the gene that exhibited the greatest degree of differential expression, and its downstream target protein p38 MAPK. The results revealed upregulation of MEK3, as well as phosphorylated MEK3 and phosphorylated p38 MAPK, in CMM patients. These results provide a "fingerprint" for mechanistic studies of CMM in the future and highlight the importance of MEK3-p38 MAPK activation in CMM.

Keywords: CACNG2; chronic pain; gene ontology; leukocytes; microarray analysis; temporomandibular disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Blotting, Western
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism
  • Chronic Pain / genetics
  • Chronic Pain / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Kinase 3 / genetics*
  • MAP Kinase Kinase 3 / metabolism
  • Male
  • Microarray Analysis
  • Middle Aged
  • Mitogen-Activated Protein Kinases / genetics*
  • Mitogen-Activated Protein Kinases / metabolism
  • Myalgia / genetics*
  • Myalgia / metabolism
  • Phosphorylation
  • Real-Time Polymerase Chain Reaction
  • Stomatognathic System / metabolism*
  • Temporomandibular Joint Disorders / genetics*
  • Temporomandibular Joint Disorders / metabolism
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • CACNG2 protein, human
  • Calcium Channels
  • GADD45G protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP2K3 protein, human