Nagata Yuki, Imanishi Yasuo, Tateishi Tomomi, Miyaoka Daichi, Kurajoh Masafumi, Arnold Andrew, Emoto Masanori
Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
J Endocr Soc. 2022 Feb 18;6(4):bvac027. doi: 10.1210/jendso/bvac027. eCollection 2022 Apr 1.
Parathyroid hormone (PTH) increases fibroblast growth factor 23 (FGF23), mediated both by protein kinase A (PKA) and Wnt signaling, and decreases expression of sclerostin, a Wnt antagonist derived from osteocytes. Patients with primary hyperparathyroidism (PHPT) have lower serum sclerostin levels than healthy controls, consistent with the idea of downregulation by PTH. Nevertheless, the relationship between FGF23 and sclerostin in PHPT is still unclear. We examined this issue in a mouse model of PHPT. PHPT mice had increased FGF23 and decreased sclerostin expression in calvaria and in their serum concentrations compared with wild-type (WT) mice. In UMR106 osteoblasts, PTH increased expression and decreased expression, as well as forskolin, a PKA agonist, whereas inhibition of PKA reversed the changes in and expression, stimulated by PTH. Sclerostin treatment had no effect on expression, but when it was added together with PTH, it statistically significantly abrogated the increase in expression. By contrast, there was no statistically significant correlation between serum FGF23 and sclerostin, whereas PTH was positively and negatively correlated with serum FGF23 and sclerostin, respectively. These results indicate that the high level of PTH in PHPT mice leads to increased FGF23 and decreased sclerostin expression in serum and calvaria. A decrease of sclerostin may further augment FGF23 in vitro; however, there was no statistically significant association between circulating FGF23 and sclerostin. It is suggested that the pathogenesis of increased FGF23 expression in PHPT mice may be modified by not only sclerostin, but also other regulatory factors modulated by PTH.
甲状旁腺激素（PTH）可增加成纤维细胞生长因子23（FGF23），这一过程由蛋白激酶A（PKA）和Wnt信号传导介导，同时PTH可降低骨细胞分泌的Wnt拮抗剂硬化蛋白的表达。原发性甲状旁腺功能亢进症（PHPT）患者的血清硬化蛋白水平低于健康对照者，这与PTH下调硬化蛋白的观点一致。然而，PHPT中FGF23与硬化蛋白之间的关系仍不清楚。我们在PHPT小鼠模型中研究了这个问题。与野生型（WT）小鼠相比，PHPT小鼠颅骨中FGF23增加，硬化蛋白表达及血清浓度降低。在UMR106成骨细胞中，PTH以及PKA激动剂福斯高林均可增加 表达并降低 表达，而抑制PKA可逆转PTH刺激引起的 和 表达变化。硬化蛋白处理对 表达无影响，但与PTH共同添加时，可在统计学上显著消除 表达的增加。相比之下，血清FGF23与硬化蛋白之间无统计学显著相关性，而PTH分别与血清FGF23和硬化蛋白呈正相关和负相关。这些结果表明，PHPT小鼠中高水平的PTH导致血清和颅骨中FGF23增加，硬化蛋白表达降低。体外实验中，硬化蛋白减少可能会进一步增加FGF23；然而，循环FGF23与硬化蛋白之间无统计学显著关联。提示PHPT小鼠中FGF23表达增加的发病机制可能不仅受硬化蛋白影响，还受PTH调节的其他调控因子影响。
