# Sialin-STAT3 axis regulates bone homeostasis in mice

## TL;DR

A new pathway involving Sialin and STAT3 in mitochondria helps maintain bone health in mice, and dietary nitrate can restore this pathway to prevent osteoporosis.

## Contribution

The study identifies a novel Sialin-STAT3 signaling axis in mitochondria that regulates bone homeostasis and responds to dietary nitrate.

## Key findings

- Sialin deficiency impairs mesenchymal stem cell function and disrupts bone homeostasis.
- Sialin promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity.
- Dietary nitrate restores Sialin expression in aged mice, preventing osteoporosis.

## Abstract

Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3S727 to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis—nitrate-Sialin-pSTAT3S727—that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.