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<p>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 <i>Mapk14</i>, 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月13日

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  • Zong Chen,
  • Zhiyou Chen,
  • Xinyan Chen,
  • Yingying Yue,
  • Yu Wang,
  • Xueying Hou,
  • Xiaoshuang Guo,
  • Chenzhi Lai,
  • Guodong Song,
  • Xiaolei Jin

摘要

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.