Runx2 Regulates Galnt3 and Fgf23 Expressions and Galnt3 Decelerates Osteoid Mineralization by Stabilizing Fgf23

Qing Jiang; Xin Qin; Takeshi Moriishi; Ryo Fukuyama; Shinichi Katsumata; Hiroshi Matsuzaki; Hisato Komori; Yuki Matsuo; Chiharu Sakane; Kosei Ito; Hironori Hojo; Shinsuke Ohba; Toshihisa Komori

doi:10.3390/ijms25042275

Runx2 Regulates Galnt3 and Fgf23 Expressions and Galnt3 Decelerates Osteoid Mineralization by Stabilizing Fgf23

Int J Mol Sci. 2024 Feb 14;25(4):2275. doi: 10.3390/ijms25042275.

Authors

Qing Jiang^{1

2}, Xin Qin^{1

2}, Takeshi Moriishi³, Ryo Fukuyama⁴, Shinichi Katsumata⁵, Hiroshi Matsuzaki⁵, Hisato Komori², Yuki Matsuo^{2

3}, Chiharu Sakane⁶, Kosei Ito², Hironori Hojo⁷, Shinsuke Ohba⁸, Toshihisa Komori²

Affiliations

¹ Institute of Orthopaedics, Suzhou Medical College, Soochow University, Suzhou 215006, China.
² Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
³ Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
⁴ Laboratory of Pharmacology, Hiroshima International University, Kure 737-0112, Japan.
⁵ Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.
⁶ Research Center for Biomedical Models and Animal Welfare, Nagasaki University, Nagasaki 852-8523, Japan.
⁷ Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
⁸ Department of Tissue and Developmental Biology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.

Abstract

Runx2 (runt related transcription factor 2) is an essential transcription factor for osteoblast proliferation and differentiation. Uridine diphosphate (UDP)-N-acetylgalactosamine (GalNAc): polypeptide GalNAc-transferase 3 (Galnt3) prevents proteolytic processing of fibroblast growth factor 23 (Fgf23), which is a hormone that regulates the serum level of phosphorus. Runx2 and Galnt3 were expressed in osteoblasts and osteocytes, and Fgf23 expression was restricted to osteocytes in bone. Overexpression and knock-down of Runx2 upregulated and downregulated, respectively, the expressions of Galnt3 and Fgf23, and Runx2 directly regulated the transcriptional activity of Galnt3 in reporter assays. The expressions of Galnt3 and Fgf23 in osteoblast-specific Runx2 knockout (Runx2^fl/flCre) mice were about half those in Runx2^fl/fl mice. However, the serum levels of phosphorus and intact Fgf23 in Runx2^fl/flCre mice were similar to those in Runx2^fl/fl mice. The trabecular bone volume was increased during aging in both male and female Galnt3^-/- mice, but the osteoid was reduced. The markers for bone formation and resorption in Galnt3^-/- mice were similar to the control in both sexes. Galnt3^-/- mice exhibited hyperphosphatemia and hypercalcemia, and the intact Fgf23 was about 40% that of wild-type mice. These findings indicated that Runx2 regulates the expressions of Galnt3 and Fgf23 and that Galnt3 decelerates the mineralization of osteoid by stabilizing Fgf23.

Keywords: Fgf23; Galnt3; Runx2; hyperphosphatemia; mineralization; osteocyte; osteoid; phosphorus.

MeSH terms

Animals
Calcification, Physiologic*
Calcinosis* / metabolism
Core Binding Factor Alpha 1 Subunit / genetics
Female
Fibroblast Growth Factors / metabolism
Male
Mice
N-Acetylgalactosaminyltransferases* / genetics
N-Acetylgalactosaminyltransferases* / metabolism
Osteoblasts* / metabolism
Phosphorus
Polypeptide N-acetylgalactosaminyltransferase

Substances

Core Binding Factor Alpha 1 Subunit
Fibroblast Growth Factors
N-Acetylgalactosaminyltransferases
Phosphorus
Polypeptide N-acetylgalactosaminyltransferase
Runx2 protein, mouse

Grants and funding

This research was funded by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology to X.Q. (Grant number: 19K24124), T.M. (23K09120), H.K. (23K08591), Y.M. (21K09819), C.S. (22K11805), and T.K. (18H05283); Key Laboratory of Orthopaedics of Suzhou (SZS2022017), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Suzhou Medical College of Soochow University to Q.J. (YXY2304045) and X.Q. (YXY2304047).