# P38α MAPK-induced senescence in cranial suture progenitor cells promotes craniosynostosis

## TL;DR

This study shows that p38α MAPK-induced cell aging in cranial suture cells causes craniosynostosis, and blocking p38 MAPK can reduce the condition in mice.

## Contribution

The study identifies p38α MAPK-induced senescence in suture progenitor cells as a novel mechanism driving craniosynostosis and validates it as a therapeutic target.

## Key findings

- Hyperactivation of p38α MAPK induces senescence in cranial suture progenitor cells in craniosynostosis.
- Pharmacological inhibition of p38 MAPK reduces suture fusion and intracranial pressure in mouse models.
- Senescent cells promote osteogenic differentiation of suture progenitor cells via Tgf-β1.

## Abstract

Craniosynostosis is a congenital cranial developmental disorder that frequently leads to craniofacial deformities and even neurological dysfunction. The abnormalities in cranial suture progenitor cells (SPC) are considered a key event in craniosynostosis; however, the specific mechanism remains unclear. Using a syndromic craniosynostosis mouse model, we found that hyperactivation of p38α mitogen-activated protein kinase (MAPK) induced senescence in SPC of craniosynostosis mice. Integrated analysis of datasets from human patients and murine models, combined with cellular validation, revealed that p38/p53 activation and cellular senescence were prevalent across multiple forms of craniosynostosis and corresponding experimental models. Additionally, senescent cells significantly promoted osteogenic differentiation of SPC by paracrine Tgf-β1. Through in vivo and in vitro experiments, our evidence demonstrates that pharmacological inhibition of p38 MAPK, conditional knockout of Mapk14, and scAAV-mediated shRNA knockdown differentially attenuate SPC senescence, suture fusion, and elevated intracranial pressure, while ameliorating behavioral abnormalities in craniosynostosis mouse model. The present study supports p38α MAPK as potential therapeutic target for craniosynostosis.

p38 MAPK attenuation therapy significantly alleviated senescence of suture progenitor cells and craniosynostosis.