# FGF23 and Cell Stress in SaOS-2 Cells—A Model Reflecting X-Linked Hypophosphatemia Dynamics

## TL;DR

This study explores how overexpression of FGF23 in SaOS-2 cells causes cellular stress and changes in cell structure, offering insights into skeletal diseases like X-linked hypophosphatemia.

## Contribution

The study reveals new mechanistic links between FGF23 signaling, endoplasmic reticulum stress, and apoptosis in skeletal disease models.

## Key findings

- FGF23 overexpression leads to enlarged and elongated rough endoplasmic reticulum and mitochondria with increased contact zones.
- Cells showed higher apoptosis rates and upregulated ER stress proteins like CHOP, XBP1, GRP94, eIF2α, and BAX.
- The findings suggest robust activation of the unfolded protein response and apoptotic pathways due to FGF23 overexpression.

## Abstract

Our study investigates the impact of FGF23 overexpression on SaOS-2 cells to elucidate its role in cellular stress and morphology, contributing to the understanding of skeletal pathologies like X-linked hypophosphatemia (XLH). Using transmission electron microscopy and protein analysis (Western blot), we analyzed the rough endoplasmic reticulum (rER) and mitochondria in SaOS-2 cells with FGF23 overexpression compared to controls. We found significant morphological changes, including enlarged and elongated rER and mitochondria, with increased contact zones, suggesting enhanced interaction and adaptation to elevated protein synthesis and secretion demands. Additionally, we observed higher apoptosis rates of the cells after 24–72 h in vitro and upregulated proteins associated with ER stress and apoptosis, such as CHOP, XBP1 (spliced and unspliced), GRP94, eIF2α, and BAX. These findings indicate a robust activation of the unfolded protein response (UPR) and apoptotic pathways due to FGF23 overexpression. Our results highlight the critical role of ER and mitochondrial interactions in cellular stress responses and provide new insights into the mechanistic link between FGF23 signaling and cellular homeostasis. In conclusion, our study underscores the importance of analyzing UPR-related pathways in the development of therapeutic strategies for skeletal and systemic diseases and contributes to a broader understanding of diseases like XLH.