PIK3R3 regulates differentiation and senescence of periodontal ligament stem cells and mitigates age-related alveolar bone loss by modulating FOXO1 expression

作者：Xuenan Liu, Donghao Wei, Feilong Wang, Fanyu Yan, Xiao Zhang, Yongsheng Zhou, Ping Zhang, Yunsong Liu · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.01.031 · 被引用次数：6 · 研究领域：FOXO transcription factor regulation、Bone Metabolism and Diseases、Oral microbiology and periodontitis research

INTRODUCTION: Periodontal diseases are prevalent among middle-aged and elderly individuals. There's still no satisfactory solution for tooth loss caused by periodontal diseases. Human periodontal ligament stem cells (hPDLSCs) is a distinctive subgroup of mesenchymal stem cells, which play a crucial role in periodontal supportive tissues, but their application value hasn't been fully explored yet. As a regulatory subunit of PI3K, PIK3R3's role in stem cell regulation remains poorly comprehended. OBJECTIVES: This study aims to explore the regulatory effect of PIK3R3 on differentiation and senescence of hPDLSCs and the underlying mechanism, as well as whether overexpression of PIK3R3 mitigate alveolar bone loss in aged rats. METHODS: Human PDLSC lines with both PIK3R3 knockdown and overexpression are established. Osteogenic, adipogenic, chondrogenic and senescent induction are used to test the effect of PIK3R3 on senescence in vitro. Model of alveolar bone loss in aged mice is used to reveal the effect of PIK3R3 in vivo. FOXO1 siRNA is used for mechanism exploration. RESULTS: Knockdown of PIK3R3 inhibits the mRNA and protein expression of markers in osteogenic, adipogenic, and chondrogenic differentiation of hPDLSCs but promotes in vitro senescence of hPDLSCs, including senescence markers expression, telomerase density and reactive oxygen species. Overexpression of PIK3R3 has the opposite effect. Furthermore, the result of Micro-CT and tissue section shows that overexpression of...