ENPP1 and CACNA2D1 associate with TMD-related Masticatory Muscle Pain

Objectives: We have investigated an orthognathic surgery population being treated for correction of malocclusion, to determine how variation in masticatory muscle gene expression and genotype associate with the presence of TMD-related myalgia. We determined masseter muscle expression differences for CACNA2D1 - alpha-2/delta-1 (α₂ϐ-1) subunit of voltage-dependent calcium channels (Ca_v), active in nociception transmission and SNP genotypes for ENPP1, a member of the ectonucleotide pyrophosphatase ephosphodiesterase family which mediate insulin resistance and bone mineralization during growth.
Methods:
After obtaining masseter muscle and saliva-DNA samples from 160 subjects during orthognathic surgery, we identified associations between genotype and muscle gene expression using TaqMan chemistry. The Jaw Pain and Function questionnaire and clinical examinations were used to diagnose TMD.
Results: Fifty one subjects had a positive diagnosis for TMD, 46 female and 5 male, which most often resulted from symptoms of muscle pain. Of the four SNPs genotyped for ENPP1, one of these - rs858339 had a significant association with TMD (p = 0.007). Quantitative RT-PCR experiments confirmed differential expression in masseter muscle for CACNA2D1. Women had higher CACNA2D1 expression then men (p = 0.0008) and women with myalgia had higher expression than those without pain (p = 0.05).
Conclusions: These results indicate that ENPP1 rs858339 genotypes contribute to development of TMD-related muscle pain through mechanisms that are at present unknown. However, two possibilities for ENPP1 biologic effects should be explored: insulin resistance which results in skeletal muscle fiber type differences and variations in bone mineralization may predispose individuals to musculoskeletal susceptibility for TMD. Our population of dentofacial deformity subjects, especially the females, has a high prevalence for TMD, which may result from differential expression of nociception mediators in skeletal muscle.