The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition
- University of Michigan, United States
- Aarhus University, Denmark
- Xiamen University, China
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
Funding
National Science Foundation (IOS-1557850)
- Cunming Duan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
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).
Version history
- Received: September 30, 2019
- Accepted: April 11, 2020
- Accepted Manuscript published: April 15, 2020 (version 1)
- Accepted Manuscript updated: April 16, 2020 (version 2)
- Version of Record published: April 27, 2020 (version 3)
- 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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The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition
eLife 9:e52322.
https://doi.org/10.7554/eLife.52322
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