Parathyroid Hormone Regulates Circulating Levels of Sclerostin and FGF23 in a Primary Hyperparathyroidism Model

Yuki Nagata; Yasuo Imanishi; Tomomi Tateishi; Daichi Miyaoka; Masafumi Kurajoh; Andrew Arnold; Masanori Emoto

doi:10.1210/jendso/bvac027

Parathyroid Hormone Regulates Circulating Levels of Sclerostin and FGF23 in a Primary Hyperparathyroidism Model

J Endocr Soc. 2022 Feb 18;6(4):bvac027. doi: 10.1210/jendso/bvac027. eCollection 2022 Apr 1.

Authors

Yuki Nagata^{1

2

3}, Yasuo Imanishi¹, Tomomi Tateishi¹, Daichi Miyaoka¹, Masafumi Kurajoh¹, Andrew Arnold⁴, Masanori Emoto¹

Affiliations

¹ Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
² Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
³ Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
⁴ Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, Connecticut 06032, USA.

Abstract

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 SOST 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 Fgf23 expression and decreased Sost expression, as well as forskolin, a PKA agonist, whereas inhibition of PKA reversed the changes in Fgf23 and Sost expression, stimulated by PTH. Sclerostin treatment had no effect on Fgf23 expression, but when it was added together with PTH, it statistically significantly abrogated the increase in Fgf23 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.

Keywords: Wnt signaling; fibroblast growth factor 23; parathyroid hormone; protein kinase A; sclerostin.