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A Hedgehog–Foxf axis coordinates dental follicle-derived alveolar bone formation

Author

Listed:
  • Mizuki Nagata

    (University of Texas Health Science Center at Houston School of Dentistry
    Institute of Science Tokyo)

  • Gaurav T. Gadhvi

    (University of Michigan)

  • Taishi Komori

    (University of Texas Health Science Center at Houston School of Dentistry)

  • Yuki Arai

    (University of Texas Health Science Center at Houston School of Dentistry)

  • Chiaki Tsutsumi-Arai

    (University of Texas Health Science Center at Houston School of Dentistry)

  • Angel Ka Yan Chu

    (University of Michigan)

  • Seth N. Nye

    (University of Michigan School of Dentistry)

  • Yuntao Yang

    (University of Texas Health Science Center at Houston)

  • Shion Orikasa

    (University of Texas Health Science Center at Houston School of Dentistry)

  • Akira Takahashi

    (Kyushu University)

  • Peter Carlsson

    (University of Gothenburg)

  • W. Jim Zheng

    (University of Texas Health Science Center at Houston)

  • Joshua D. Welch

    (University of Michigan
    University of Michigan)

  • Noriaki Ono

    (University of Texas Health Science Center at Houston School of Dentistry)

  • Wanida Ono

    (University of Texas Health Science Center at Houston School of Dentistry
    University of California San Francisco School of Dentistry)

Abstract

The alveolar bone is a specialized mineralized structure supporting the lifelong functionality of the tooth in mastication. The alveolar bone develops from the dental follicle (DF) during tooth root formation due to deliberate epithelial–mesenchymal interactions. However, how DF progenitor cell fates are regulated toward alveolar bone osteoblasts remains unknown. We find that Hedgehog signaling activities are transiently activated during the onset of tooth root formation and alveolar bone formation. Parathyroid hormone-related protein (PTHrP)-expressing DF cells are highly responsive to Hedgehog signaling, yet constitutive Hedgehog activation using Pthrp-creER and Ptch1-floxed alleles potently suppresses alveolar osteoblast and ligament differentiation of PTHrP+ DF cells, resulting in striking susceptibility to alveolar bone loss. Concomitant inactivation of Hedgehog-target Foxf1 factor in Hedgehog-activated PTHrP+ DF cells partially rescued alveolar bone defects. Therefore, the Hedgehog–Foxf pathway needs to be suppressed to drive alveolar bone osteoblast fates of PTHrP+ DF cells, unraveling a unique tooth-specific mechanism of bone formation requiring deliberate on-off regulations of Hedgehog signaling.

Suggested Citation

  • Mizuki Nagata & Gaurav T. Gadhvi & Taishi Komori & Yuki Arai & Chiaki Tsutsumi-Arai & Angel Ka Yan Chu & Seth N. Nye & Yuntao Yang & Shion Orikasa & Akira Takahashi & Peter Carlsson & W. Jim Zheng & J, 2025. "A Hedgehog–Foxf axis coordinates dental follicle-derived alveolar bone formation," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61050-3
    DOI: 10.1038/s41467-025-61050-3
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    References listed on IDEAS

    as
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