Hepcidin promotes oral ulcer healing via amphiregulin production in rats

Background/purpose: Hepcidin is an antimicrobial peptide that regulates iron metabolism. Recently, hepcidin was reported to promote wound healing. However, the mechanism underlying hepcidin signaling in the oral mucosa remains unclear. In the present study, we examined the mechanism by which hepcidin accelerates healing in a rat model of oral ulcerative mucositis. Materials and methods: In male Wistar rats, 50 % acetic acid was applied to the labial fornix region of the inferior incisors to create a model of oral ulcerative mucositis. The ulcerative mucositis severity was evaluated using an oral mucositis score. Hepcidin expression, phosphorylation of the hepcidin receptor ferroportin and the levels of the epidermal growth factor amphiregulin were assessed using immunohistochemistry and western blotting. Hepcidin was applied to the oral mucosal region of rats with exacerbated oral ulcerative mucositis, which developed following acetic acid treatment after extraction of the submandibular and sublingual glands. Results: Two and five days after acetic acid treatment, hepcidin levels increased in the ulcerated region and saliva. Ferroportin in the ulcerated region was phosphorylated 2 days after acetic acid treatment. The expression and amount of amphiregulin in the ulcerated region increased on days 2 and 5. In exacerbated oral ulcerative mucositis rats, the oral ulcerative mucositis healing period was prolonged, and hepcidin and amphiregulin levels in the ulcerated region decreased. Daily hepcidin application to the ulcerated region shortened the healing period in exacerbated oral ulcerative mucositis rats. Conclusion: Oral ulcerative mucositis-induced increase in hepcidin promotes healing through the amphiregulin production of via ferroportin activation.