1. Developmental Biology
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The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

  1. Chengdong Liu
  2. Shuang Li
  3. Pernille Rimmer Noer
  4. Kasper Kjaer-Sorensen
  5. Anna Karina Juhl
  6. Allison Goldstein
  7. Caihuan Ke
  8. Claus Oxvig  Is a corresponding author
  9. Cunming Duan  Is a corresponding author
  1. University of Michigan, United States
  2. Aarhus University, Denmark
  3. Xiamen University, China
Research Article
  • Cited 1
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Cite this article as: eLife 2020;9:e52322 doi: 10.7554/eLife.52322
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Abstract

Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates bone calcification by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which are normally quiescent, re-enter the cell cycle under low [Ca2+] stress. Genetic deletion of Papp-aa, but not the closely related Papp-ab, abolished ionocyte proliferation and reduced calcified bone mass. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling in ionocytes. Under low Ca2+ stress, Papp-aa cleaved Igfbp5a. Under normal conditions, however, Papp-aa proteinase activity was suppressed and IGFs were sequestered in the IGF/Igfbp complex. Pharmacological disruption of the IGF/Igfbp complex or adding free IGF1 activated IGF signaling and promoted ionocyte proliferation. These findings suggest that Papp-aa-mediated local Igfbp5a cleavage functions as a [Ca2+]-regulated molecular switch linking IGF signaling to bone calcification by stimulating epithelial cell quiescence-proliferation transition under low Ca2+ stress.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chengdong Liu

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shuang Li

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pernille Rimmer Noer

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  4. Kasper Kjaer-Sorensen

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Karina Juhl

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Allison Goldstein

    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Caihuan Ke

    College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Claus Oxvig

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    For correspondence
    co@mb.au.dk
    Competing interests
    The authors declare that no competing interests exist.
  9. Cunming Duan

    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    For correspondence
    cduan@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6794-2762

Funding

National Science Foundation (IOS-1557850)

  • Cunming Duan

Lundbeck (Grant R317-2019-526)

  • Claus Oxvig

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

Ethics

Animal experimentation: All experiments were conducted in accordance with the guidelines approved by the Institutional Committee on the Use and Care of Animals, University of Michigan and the Danish The Animal Experiments Inspectorate (permit numbers 2017-15-0201-01369 and 2017-15-0202-00098).

Reviewing Editor

  1. Cheryl Ackert-Bicknell, University of Colorado, United States

Publication history

  1. Received: September 30, 2019
  2. Accepted: April 11, 2020
  3. Accepted Manuscript published: April 15, 2020 (version 1)
  4. Accepted Manuscript updated: April 16, 2020 (version 2)
  5. Version of Record published: April 27, 2020 (version 3)
  6. Version of Record updated: May 15, 2020 (version 4)

Copyright

© 2020, 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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