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Background <p>Periodontal ligament stem cells (PDLSCs) are essential for periodontal tissue regeneration, but their osteogenic differentiation is significantly impaired in the inflammatory microenvironment of periodontitis. This study aimed to investigate the regulatory role of the SENP6-SMAD5-SOX2 axis in PDLSC osteogenesis.</p> Methods <p>Transcriptomic analysis of public datasets was used to identify key regulators. In vitro functional experiments, including siRNA-mediated knockdown, co-immunoprecipitation, and luciferase assays, were performed on PDLSCs isolated from healthy donors. The expression of SOX2 and early osteogenic markers (ALP and RUNX2) was assessed at day 7 of osteogenic induction. In vivo, the SENP6 inhibitor NSC632839 was evaluated in an LPS-induced mouse calvarial osteolysis model via micro-CT and H&amp;E histological assessment.</p> Results <p>In periodontitis tissues, SMAD5 protein was downregulated despite mRNA upregulation. In healthy PDLSCs, SENP6 knockdown stabilized SMAD5 protein and significantly upregulated the expression of SOX2 and early osteogenic markers ALP and RUNX2. Mechanistically, SMAD5 directly activated SOX2 transcription. In the mouse calvarial model, NSC632839 treatment effectively promoted bone formation and increased the bone volume fraction (BV/TV) through SOX2 upregulation, while the SMAD5 inhibitor CDD1653 exacerbated bone loss.</p> Conclusions <p>The SENP6-SMAD5-SOX2 axis is a critical regulator of early PDLSC osteogenic commitment. Pharmacological inhibition of SENP6 offers a promising therapeutic strategy for restoring bone regeneration in inflammatory environments.</p>

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SENP6-mediated desumoylation of SMAD5 regulates osteogenic fate in periodontal ligament stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Hui Jin,
  • Chengmin Liu,
  • Wenchao Wang,
  • Huawei Xie,
  • Bo Ji,
  • Wenjia Wei,
  • Xiaofeng Wang

摘要

Background

Periodontal ligament stem cells (PDLSCs) are essential for periodontal tissue regeneration, but their osteogenic differentiation is significantly impaired in the inflammatory microenvironment of periodontitis. This study aimed to investigate the regulatory role of the SENP6-SMAD5-SOX2 axis in PDLSC osteogenesis.

Methods

Transcriptomic analysis of public datasets was used to identify key regulators. In vitro functional experiments, including siRNA-mediated knockdown, co-immunoprecipitation, and luciferase assays, were performed on PDLSCs isolated from healthy donors. The expression of SOX2 and early osteogenic markers (ALP and RUNX2) was assessed at day 7 of osteogenic induction. In vivo, the SENP6 inhibitor NSC632839 was evaluated in an LPS-induced mouse calvarial osteolysis model via micro-CT and H&E histological assessment.

Results

In periodontitis tissues, SMAD5 protein was downregulated despite mRNA upregulation. In healthy PDLSCs, SENP6 knockdown stabilized SMAD5 protein and significantly upregulated the expression of SOX2 and early osteogenic markers ALP and RUNX2. Mechanistically, SMAD5 directly activated SOX2 transcription. In the mouse calvarial model, NSC632839 treatment effectively promoted bone formation and increased the bone volume fraction (BV/TV) through SOX2 upregulation, while the SMAD5 inhibitor CDD1653 exacerbated bone loss.

Conclusions

The SENP6-SMAD5-SOX2 axis is a critical regulator of early PDLSC osteogenic commitment. Pharmacological inhibition of SENP6 offers a promising therapeutic strategy for restoring bone regeneration in inflammatory environments.