Work

Notch signaling modulates Fgf23 expression through crosstalk with hypoxia and PTH pathways in osteogenic cells

Year: 2025

Type: article

Abstract: Fibroblast growth factor 23 (Fgf23) is produced by bone and functions primarily as a phosphaturia hormone. We previously reported that overexpression of the Notch intracellular domain (NICD) in osteogenic cells enhances Fgf23 expression in association with osteomalacia in vivo. Here, we investigated the underlying mechanisms using osteogenic cell lines UMR-106 and IDG-SW3 cells. NICD overexpression increased Fgf23 levels in both cell types. Manipulating RBPJ-κ activity, either a dominant-negative or constitutively active form, revealed that Notch-mediated Fgf23 expression is dependent on RBPJ-κ. Treatment with iron chelator Desferrioxamine (DFO) upregulated Fgf23 expression, which was abolished by dominant-negative RBPJ-κ overexpression. This effect was partially attenuated by short hairpin RNA (shRNA) targeting hypoxia-inducible factor (HIF)-2α, but not HIF-1α. DFO treatment also increased expression of Notch1 protein, but not Notch2 and Nocth3, in parallel with upregulation of the Notch target mRNAs, Hes1 and Hey1. In addition, DFO elevated the expression of γ-secretase subunits, whereas a γ-secretase inhibitor suppressed DFO-induced increases in Notch1 and Fgf23 levels, suggesting that increased γ-secretase expression promotes Notch processing. Moreover, Notch signaling exerted an additive stimulatory effect on parathyroid hormone (PTH)-induced Fgf23 expression, at least in part through interaction with the protein kinase A (PKA) pathway. Co-immunoprecipitation assays revealed a physical interaction between NICD and CREB. Collectively, these findings demonstrate that Notch signaling regulates Fgf23 expression through crosstalk with hypoxic and PTH pathways, providing novel insights into Fgf23 regulation and identifying potential therapeutic targets for Fgf23-related disorders.

Source: Molecular and Cellular Endocrinology

DOI: 10.1016/j.mce.2025.112663

Authors: Yoshihiro Tamamura, Kenta Terai, Akira Yamaguchi

Institutions: Tokyo Dental College, Tokushima University

Language: English

Topic: Parathyroid Disorders and Treatments

Subfield: Nephrology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,510