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3D MAPs discovers the morphological sequence chondrocytes undergo in the growth plate and the regulatory role of GDF5 in this process

Sarah Rubin, Ankit Agrawal, Johannes Stegmaier, Jonathan Svorai, Yoseph Addadi, Paul Villoutreix, View ORCID ProfileTomer Stern, Elazar Zelzer
doi: https://doi.org/10.1101/2020.07.28.225409
Sarah Rubin
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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Ankit Agrawal
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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Johannes Stegmaier
2Institute of Imaging and Computer Vision, RWTH Aachen University, Aachen, Germany
3Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany
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Jonathan Svorai
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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Yoseph Addadi
4Department of Life Science Core Facilities, Weizmann Institute of Science, Rehovot, 76100, Israel
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Paul Villoutreix
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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  • For correspondence: Eli.Zelzer@weizmann.ac.il tstern@princeton.edu paul.villoutreix@univ-amu.fr
Tomer Stern
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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  • ORCID record for Tomer Stern
  • For correspondence: Eli.Zelzer@weizmann.ac.il tstern@princeton.edu paul.villoutreix@univ-amu.fr
Elazar Zelzer
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel
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  • For correspondence: Eli.Zelzer@weizmann.ac.il tstern@princeton.edu paul.villoutreix@univ-amu.fr
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Abstract

The activity of the epiphyseal growth plates, which drive longitudinal growth of long bones, is dependent on the ability of chondrocytes to change their shape and size extensively as they differentiate. However, organ size, extracellular matrix density and cell number have hindered the study of chondrocyte morphology. Here, we describe a new pipeline called 3D Morphometric Analysis for Phenotypic significance (3D MAPs), which overcomes these obstacles. By using 3D MAPs, we have created an image database of hundreds of thousands of cells from orthologous long bones. Analysis of this database revealed the growth strategies that chondrocytes use during differentiation. We found that chondrocytes employed both allometric and isometric growth, and that allometric growth is achieved by changes either in volume or surface area along a specific cell axis in a zone-specific manner. Additionally, we discovered a new organization of chondrocytes within the growth plate, where cells are orientated such that their longest axis always aligns with the dorsal-ventral axis of the bone. To demonstrate the ability of 3D MAPs to explore mechanisms of growth plate regulation, we studied the abnormally short tibiae of Gdf5-null mice. 3D MAPs identified aberrant cellular growth behaviors which resulted in a 3-fold reduction in volumetric cell growth, as well as affected cell morphology and orientation, highlighting GDF5 as a new regulator of growth plate activity. Overall, our findings provide new insight into the morphological sequence that chondrocytes undergo during differentiation and highlight the ability of 3D MAPs to uncover molecular and cellular mechanisms regulating this process. More broadly, this work provides a new framework for studying growth plate biology.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 28, 2020.
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3D MAPs discovers the morphological sequence chondrocytes undergo in the growth plate and the regulatory role of GDF5 in this process
Sarah Rubin, Ankit Agrawal, Johannes Stegmaier, Jonathan Svorai, Yoseph Addadi, Paul Villoutreix, Tomer Stern, Elazar Zelzer
bioRxiv 2020.07.28.225409; doi: https://doi.org/10.1101/2020.07.28.225409
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3D MAPs discovers the morphological sequence chondrocytes undergo in the growth plate and the regulatory role of GDF5 in this process
Sarah Rubin, Ankit Agrawal, Johannes Stegmaier, Jonathan Svorai, Yoseph Addadi, Paul Villoutreix, Tomer Stern, Elazar Zelzer
bioRxiv 2020.07.28.225409; doi: https://doi.org/10.1101/2020.07.28.225409

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