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

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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. 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. 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. 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 cell proliferation, 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 PIK3R3 in elder rats mitigates alveolar bone loss. Mechanistically, PIK3R3 regulates senescence of hPDLSCs through modulating FOXO1 expression. Expression of FOXO1 is altered when PIK3R3 is knocked down or overexpressed in senescent medium. Knockdown of FOXO1 promotes senescence of hPDLSCs and the senescence promoting effect of knocking down PIK3R3 is weakened when FOXO1 is highly expressed. These findings indicate that PIK3R3 modulates senescence of MSCs by regulating FOXO1 expression and shows promise as a therapeutic target for mitigating age-related alveolar bone loss.