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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We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibroblast growth factor (FGF) signaling in germ layer specification and head-to-tail development of Xenopus embryos. Here, we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte, and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endogenous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection of Sdc4 mRNA partially rescued NC migration defects induced by both HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism:
SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration.
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- Developmental Biology
- Neuroscience
Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.
