Secondary ossification center induces and protects growth plate structure
- Karolinska Institutet, Sweden
- Schmalhausen Institute of Zoology of NAS of Ukraine, Ukraine
- Uppsala University, Evolutionary Biology Centre, Sweden
- Sechenov University, Russian Federation
- University of California San Diego, United States
- Massachusetts General Hospital and Harvard Medical School, United States
- University of Vienna, Austria
- Medical University of Vienna, Austria
- KTH Royal Institute of Technology, Sweden
- European Synchrotron Radiation Facility, France
- Univeristy of California, San Diego, United States
Abstract
Growth plate and articular cartilage constitute a single anatomical entity early in development, but later separate into two distinct structures by the secondary ossification center (SOC). The reason for such separation remains unknown. We found that evolutionarily SOC appears in animals conquering the land - amniotes. Analysis of ossification pattern in mammals with specialized extremities (whales, bats, jerboa) revealed that SOC development correlates with the extent of mechanical loads. Mathematical modelling revealed that SOC reduces mechanical stress within the growth plate. Functional experiments revealed high vulnerability of hypertrophic chondrocytes to mechanical stress and showed that SOC protects these cells from apoptosis caused by extensive loading. Atomic force microscopy showed that hypertrophic chondrocytes are the least mechanically stiff cells within the growth plate. Altogether, these findings suggest that SOC has evolved to protect the hypertrophic chondrocytes from the high mechanical stress encountered in the terrestrial environment.
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
EMBO
- Meng Xie
- Igor Adameyko
Svenska Forskningsrådet Formas
- Sophie Sanchez
- Igor Adameyko
- Andrei S Chagin
Russian Science Foundation
- Peter Timashev
Stiftelsen Frimurare Barnhuset i Stockholm
- Meng Xie
- Phillip T Newton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Xu Cao, Johns Hopkins University School of Medicine, United States
Ethics
Animal experimentation: all animal experiments were pre-approved by the Ethical Committee on Animal Experiments (N5/16, N187/15, 9091-2018, Stockholm North Committee/ Norra Djurförsöksetiska Nämnden), the Institutional Animal Care and Use Committee of the Massachusetts General Hospital (Protocols #: 2005N000094 and 2004N000176) or the University of California San Diego (D16-00020) and conducted in accordance with the provisions and guidelines for animal experimentation formulated by the Swedish Animal Agency. Animal experiments involving limb unloading, AFM and nanoindentation were pre-approved by the Ethics Committee of the Sechenov First State Moscow Medical University (No. 07-17 from 13.09.2017, Moscow, Russia).
Version history
- Received: January 16, 2020
- Accepted: October 9, 2020
- Accepted Manuscript published: October 16, 2020 (version 1)
- Version of Record published: October 22, 2020 (version 2)
Copyright
© 2020, Xie 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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Secondary ossification center induces and protects growth plate structure
eLife 9:e55212.
https://doi.org/10.7554/eLife.55212
Further reading
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Amniogenesis, a process critical for continuation of healthy pregnancy, is triggered in a collection of pluripotent epiblast cells as the human embryo implants. Previous studies have established that bone morphogenetic protein (BMP) signaling is a major driver of this lineage specifying process, but the downstream BMP-dependent transcriptional networks that lead to successful amniogenesis remain to be identified. This is, in part, due to the current lack of a robust and reproducible model system that enables mechanistic investigations exclusively into amniogenesis. Here, we developed an improved model of early amnion specification, using a human pluripotent stem cell-based platform in which the activation of BMP signaling is controlled and synchronous. Uniform amniogenesis is seen within 48 hr after BMP activation, and the resulting cells share transcriptomic characteristics with amnion cells of a gastrulating human embryo. Using detailed time-course transcriptomic analyses, we established a previously uncharacterized BMP-dependent amniotic transcriptional cascade, and identified markers that represent five distinct stages of amnion fate specification; the expression of selected markers was validated in early post-implantation macaque embryos. Moreover, a cohort of factors that could potentially control specific stages of amniogenesis was identified, including the transcription factor TFAP2A. Functionally, we determined that, once amniogenesis is triggered by the BMP pathway, TFAP2A controls the progression of amniogenesis. This work presents a temporally resolved transcriptomic resource for several previously uncharacterized amniogenesis states and demonstrates a critical intermediate role for TFAP2A during amnion fate specification.
