Pain-associated Mediators and Axon Pathfinders in Fibromyalgia Skin Cells

Objective.To investigate whether the expression of cytokine, nociception-associated ion channel, and axon guidance genes in patients with skin cell fibromyalgia syndrome (FMS) 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 quantitative real-time PCR.Results.In fibroblasts, transforming growth factor–ß1 (TGF-ß1) gene expression was higher in patients with FMS compared to controls (calf and thigh: p < 0.001). Also, expression was higher in patients than in controls for these variables: hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (calf: p < 0.01), ephrin-A4 (EFNA4; calf: p < 0.05, thigh: p < 0.001), and ephrin receptor-A4 (EPHA4; thigh: p < 0.05). In keratinocytes, interleukin 10 gene expression was higher in patients with FMS 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 patients with FMS 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.