Pain-associated mediators and axon pathfinders in fibromyalgia skin cells

Dimitar Evdokimov, Luisa Kreß, Philine Dinkel, Johanna Frank, Claudia Sommer, Nurcan Üçeyler
Journal of Rheumatology 2019 June 15

OBJECTIVE: To investigate whether the expression of cytokine, nociceptionassociated ion channel, and axon guidance genes in skin cells fibromyalgia syndrome (FMS) patients differs from healthy controls potentially contributing to pain and small fiber degeneration in FMS.

METHODS: We prospectively recruited 128 patients and 26 healthy controls. All study participants underwent neurological examination and a skin punch biopsy was obtained from the lateral calf and thigh. Skin samples were processed to histologically determine intraepidermal nerve fiber density (IENFD) and for primary fibroblast and keratinocyte cell cultures. Gene expression of selected pro- and antiinflammatory cytokines, nociception-associated ion channels, and axon guidance cues was assessed with qRT-PCR.

RESULTS: In fibroblasts, transforming growth factor-ß1 (TGF-ß1) gene expression was higher in FMS patients compared to controls (calf and thigh: p<0.001). Also, hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2) (calf: p<0.01), ephrin-A4 (EFNA4) (calf: p<0.05, thigh: p<0.001), and ephrin receptor-A4 (EPHA4) (thigh: p<0.05) expression was higher in patients than in controls. In keratinocytes, interleukin(IL-)10 gene expression was higher in FMS patients than in controls (thigh: p<0.05). While no intergroup difference was found for nociception-associated ion channels, EFNA4 and EPHA4 (calf: p<0.01 each) expression was higher in FMS patients than in controls. Axon guide expression did not correlate with IENFD.

CONCLUSION: In FMS, skin cells may contribute to cutaneous nociception by differentially expressing membrane-bound and soluble pain mediators and axon pathfinders.


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