The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

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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.

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

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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.
Shuang Li

Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Pernille Rimmer Noer

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

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The authors declare that no competing interests exist.
Kasper Kjaer-Sorensen

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

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The authors declare that no competing interests exist.
Anna Karina Juhl

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

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The authors declare that no competing interests exist.
Allison Goldstein

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

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The authors declare that no competing interests exist.
Caihuan Ke

College of Ocean and Earth Sciences, Xiamen University, Xiamen, China

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The authors declare that no competing interests exist.
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.
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.

"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).

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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.