Nakamura Takashi, Nakamura Hannah M, Iwasaki Yasumasa, Enomoto-Iwamoto Motomi, Nakashima Noriaki, Fukumoto Satoshi, Pacifici Maurizio, Iwamoto Masahiro, Wakamori Minoru
Division of Molecular Pharmacology & Cell Biophysics, Department of Disease Management Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan.
Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
FEBS J. 2025 Mar 31. doi: 10.1111/febs.70085.
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.
Epiprofin（Epfn）是一种Sp/KLF家族转录因子，可调节细胞增殖并决定细胞命运，对正常皮肤、毛囊和牙齿发育至关重要。我们发现Epfn在甲状旁腺中表达，Epfn基因敲除小鼠血清甲状旁腺激素（PTH）浓度升高、骨体积减少且出现颅内异位钙化。为研究Epfn在PTH表达调控中的作用，采用了甲状旁腺外植体和甲状旁腺细胞系培养方法。发现Epfn表达随细胞外钙浓度升高而上调，而PTH表达则下调，表明二者呈负相关。在甲状旁腺细胞中强制表达Epfn可抑制PTH基因表达和PTH启动子报告基因活性。此外，在高细胞外钙浓度条件下，培养的甲状旁腺中Epfn沉默未能阻断PTH基因表达。染色质免疫沉淀定量PCR（ChIP-qPCR）分析还揭示Epfn结合于PTH启动子近端区域，在高浓度钙离子存在时这种结合会加速。我们的体外和离体分析结果表明，Epfn是一种通过调节PTH启动子近端区域新鉴定出的PTH转录负调节因子。此外，原发性甲状旁腺功能亢进患者甲状旁腺腺瘤中Epfn表达显著降低。将Epfn鉴定为控制甲状旁腺功能亢进患者PTH产生的潜在治疗靶点，为靶向治疗方法开辟了新途径。
