1. Cell Biology
  2. Stem Cells and Regenerative Medicine

PTH regulates osteogenesis and suppresses adipogenesis through Zfp 467 in a feed-forward, PTH1R-cyclic AMP-dependent manner

  1. Hanghang Liu
  2. Akane Wada
  3. Isabella Le
  4. Phuong T Le
  5. Andrew WF Lee
  6. Jun Zhou
  7. Francesca Gori
  8. Roland Baron
  9. Clifford J Rosen  Is a corresponding author
  1. Maine Medical Center Research Institute, United States
  2. Harvard University, United States
https://doi.org/10.7554/eLife.83345
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Cite this article
  1. Hanghang Liu
  2. Akane Wada
  3. Isabella Le
  4. Phuong T Le
  5. Andrew WF Lee
  6. Jun Zhou
  7. Francesca Gori
  8. Roland Baron
  9. Clifford J Rosen
(2023)
PTH regulates osteogenesis and suppresses adipogenesis through Zfp 467 in a feed-forward, PTH1R-cyclic AMP-dependent manner
eLife 12:e83345.
https://doi.org/10.7554/eLife.83345
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Abstract

Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate towards osteogenesis and higher bone mass. PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of Zfp467 in osteogenic precursors would lead to high bone mass in mice. Prrx1Cre; Zfp467fl/fl but not AdipoqCre; Zfp467fl/fl mice exhibit high bone mass and greater osteogenic differentiation similar to the Zfp467-/- mice. qPCR results revealed that PTH suppressed Zfp467 expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of Zfp467 and gene silencing of Pth1r caused an increase in Zfp467 mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of Zfp467 resulted in higher nuclear translocation of NFκB1 that binds to the P2 promoter of the Pth1r and increased its transcription. As expected, Zfp467-/- cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in Zfp467-/- calvarial osteoblasts, and the pro-osteogenic effect of Zfp467 deletion was blocked by gene silencing of Pth1r or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of Zfp467 results in a pathway that increases Pth1r transcription via NFκB1 and thus cellular responsiveness to PTH/PTHrP, ultimately leading to enhanced bone formation.

Data availability

RNA-seq data that support the findings in this study are openly available in Sequence Read Archive database (PRJNA877934, http://www.ncbi.nlm.nih.gov/bioproject/877934).All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 3-Figure 7.

The following data sets were generated

Article and author information

Author details

  1. Hanghang Liu

    Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Akane Wada

    Department of Oral Medicine, Infection and Immunity, Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Isabella Le

    Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Phuong T Le

    Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Andrew WF Lee

    Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Jun Zhou

    Department of Oral Medicine, Infection and Immunity, Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Francesca Gori

    Department of Oral Medicine, Infection and Immunity, Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5685-8303

  8. Roland Baron

    Department of Oral Medicine, Infection and Immunity, Harvard University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Clifford J Rosen

    Maine Medical Center Research Institute, Scarborough, United States
    For correspondence
    cjrofen@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3436-8199

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK112374)

  • Clifford J Rosen

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR073774)

  • Clifford J Rosen

National Institute of Diabetes and Digestive and Kidney Diseases (DK092759)

  • Clifford J Rosen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ernestina Schipani, University of Pennsylvania, United States

Ethics

Animal experimentation: All experimental procedures were approved by the Institutional Animal Care and Use Committee of Maine Medical Center (IACUC # 1914) and followed the NIH guidelines for the Care and Use of Laboratory Animals and also approved by the Harvard University Institutional Animal Care and Use Committee.

Version history

  1. Received: September 8, 2022
  2. Preprint posted: October 10, 2022 (view preprint)
  3. Accepted: April 25, 2023
  4. Accepted Manuscript published: April 26, 2023 (version 1)
  5. Version of Record published: May 10, 2023 (version 2)

Copyright

© 2023, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hanghang Liu
  2. Akane Wada
  3. Isabella Le
  4. Phuong T Le
  5. Andrew WF Lee
  6. Jun Zhou
  7. Francesca Gori
  8. Roland Baron
  9. Clifford J Rosen
(2023)
PTH regulates osteogenesis and suppresses adipogenesis through Zfp 467 in a feed-forward, PTH1R-cyclic AMP-dependent manner
eLife 12:e83345.
https://doi.org/10.7554/eLife.83345

Share this article

https://doi.org/10.7554/eLife.83345

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