Molecular mechanism for transcriptional regulation of the parathyroid hormone gene by Epiprofin.

Abstract

Epiprofin (Epfn), an Sp/KLF family transcription factor that regulates cell proliferation and determines cell fates, is essential for normal skin, hair follicle, and tooth development. We found that Epfn was expressed in parathyroid glands, and Epfn-knockout mice displayed elevated serum parathyroid hormone (PTH) concentrations, decreased bone volume, and intracranial ectopic calcification. To investigate the role of Epfn in the regulation of PTH expression, parathyroid gland explant and parathyroid cell line culture methods were used. Epfn expression was found to be upregulated in response to an increase in extracellular calcium concentration, whereas PTH expression was downregulated, thus demonstrating an inverse correlation. Forced expression of Epfn inhibited PTH gene expression and PTH promoter reporter activity in parathyroid cells. In addition, with a high extracellular calcium concentration, Epfn silencing in cultured parathyroid glands failed to block PTH gene expression. ChIP-qPCR analysis also revealed Epfn binding in the proximal region of the PTH promoter, which was accelerated in the presence of a high concentration of calcium ions. The results from our in vitro and ex vivo analyses suggest that Epfn is a newly identified negative regulator of PTH transcription by regulating the proximal PTH promoter. Furthermore, the expression of Epfn was significantly reduced in parathyroid adenomas of primary hyperparathyroidism patients. The identification of Epfn as a potential therapeutic target for the control of PTH production in hyperparathyroidism patients opens new avenues for targeted treatment approaches.