# Epigenetic Targeting of Senescent Cells Prevents the Deleterious Effects of Obstructive Sleep Apnea on Growing Skeleton

## TL;DR

This study shows that chronic hypoxia from sleep apnea causes bone growth issues in young mice by triggering cell aging, and reversing this with a drug helps bone development.

## Contribution

The study reveals a novel epigenetic mechanism linking hypoxia to bone defects and proposes targeting histone methylation as a therapeutic strategy.

## Key findings

- CIH induces senescence in osteoprogenitors via HIF1α-mediated suppression of EZH2 and H3k27me3.
- UTX inhibition restores H3K27me3 levels and prevents CIH-induced bone growth impairment.
- Pharmacological or genetic restoration of H3K27me3 promotes osteogenesis and alleviates bone loss.

## Abstract

Obstructive Sleep Apnea Syndrome (OSAS) is a common sleep disorder characterized by chronic intermittent hypoxia (CIH), which has been increasingly recognized for its systemic effects on pediatric skeletal development. However, the mechanism by which CIH influences bone growth and homeostasis remains largely unexplored. In this study, it is demonstrated that CIH exposure in young murine models induces cellular senescence within the metaphysis of long bones, resulting in compromised bone formation and growth retardation. Through single cell sequencing and in situ immunostaining, it is identified that the senescent cells predominantly consist of osteoprogenitors. Mechanistically, CIH enhances the activity of hypoxia‐inducible factor 1‐alpha (HIF‐1α) in osteoprogenitors and subsequently downregulates trimethylation of histone H3 at lysine 27 (H3k27me3) through the suppression of polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2), thereby facilitating the expression of senescence‐associated genes. Employing both genetic and pharmacological strategies, it is demonstrated that the restoration of H3K27me3 levels via UTX inhibition (achieved through in vivo knockout or GSK‐J4 treatment) effectively prevents CIH‐induced senescence, promotes osteogenesis, and alleviates bone loss and growth retardation. These findings elucidate a novel epigenetic mechanism that underlies the skeletal impairments associated with CIH and underscore the therapeutic potential of targeting histone methylation to mitigate hypoxia‐induced bone defects.

Chronic intermittent hypoxia induces premature senescence of osteoprogenitor cells in long bone metaphysis via HIF1α‐mediated EZH2‐H3k27me3 downregulation, leading to impaired bone growth. Restoration of H3K27me3 level via UTX inhibition rescues osteogenesis and growth impairment in young mice.