PMID- 32619649
OWN - NLM
STAT- MEDLINE
DCOM- 20201208
LR  - 20201214
IS  - 1879-2596 (Electronic)
IS  - 0167-4889 (Linking)
VI  - 1867
IP  - 10
DP  - 2020 Oct
TI  - Ryanodine receptor 1 mediated dexamethasone-induced chondrodysplasia in fetal 
      rats.
PG  - 118791
LID - S0167-4889(20)30149-X [pii]
LID - 10.1016/j.bbamcr.2020.118791 [doi]
AB  - BACKGROUND: Osteoarthritis is caused by cartilage dysplasia and has fetal origin. 
      Prenatal dexamethasone exposure (PDE) induced chondrodysplasia in fetal rats by 
      inhibiting transforming growth factor beta (TGFbeta) signaling. This study aimed to 
      determine the effect of dexamethasone on fetal cartilage development and 
      illustrate the underlying molecular mechanism. METHODS: Dexamethasone 
      (0.2 mg/kg.d) was injected subcutaneously every morning in pregnant rats from 
      gestational day (GD) 9 to GD21. Harvested fetal femurs and tibias at GD21 for 
      immunofluorescence and gene expression analysis. Fetal chondrocytes were treated 
      with dexamethasone (100, 250 and 500 nM), endoplasmic reticulum stress (ERS) 
      inhibitor, and ryanodine receptor 1 (RYR1) antagonist for subsequent analyses. 
      RESULTS: In vivo, prenatal dexamethasone exposure (PDE) decreased the total 
      length of the fetal cartilage, the proportion of the proliferation area and the 
      cell density and matrix content in fetal articular cartilage. Moreover, PDE 
      increased RYR1 expression and intracellular calcium levels and elevated the 
      expression of ERS-related genes, while downregulated the TGFbeta signaling pathway 
      and extracellular matrix (ECM) synthesis in fetal chondrocytes. In vitro, we 
      verified dexamethasone significantly decreased ECM synthesis through activating 
      RYR 1 mediated-ERS. CONCLUSIONS: PDE inhibited TGFbeta signaling pathway and matrix 
      synthesis through RYR1 / intracellular calcium mediated ERS, which ultimately led 
      to fetal dysplasia. This study confirmed the molecular mechanism of ERS involved 
      in the developmental toxicity of dexamethasone and suggested that RYR1 may be an 
      early intervention target for fetal-derived adult osteoarthritis.
CI  - Copyright (c) 2020 Elsevier B.V. All rights reserved.
FAU - Wang, Yi-Zhong
AU  - Wang YZ
AD  - Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 
      430071, China; Xiangyang No.1 People' Hospital, Hubei University of Medicine, 
      Xiangyang 441000, China.
FAU - Li, Qing-Xian
AU  - Li QX
AD  - Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 
      430071, China.
FAU - Zhang, Ding-Mei
AU  - Zhang DM
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China.
FAU - Chen, Liao-Bin
AU  - Chen LB
AD  - Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan, 430071, China. Electronic address: lbchen@whu.edu.cn.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 
      430071, China; Hubei Provincial Key Laboratory of Developmentally Originated 
      Disease, Wuhan, 430071, China. Electronic address: wanghui19@whu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200630
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Cell Res
JT  - Biochimica et biophysica acta. Molecular cell research
JID - 101731731
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - 0 (Transforming Growth Factor beta)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cartilage, Articular/embryology/pathology/ultrastructure
MH  - Chondrocytes/metabolism/pathology
MH  - Dexamethasone/*adverse effects
MH  - Endoplasmic Reticulum Stress
MH  - Extracellular Matrix/metabolism
MH  - Female
MH  - Fetus/*metabolism/*pathology
MH  - Male
MH  - Osteochondrodysplasias/*chemically induced/*embryology/pathology
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects/pathology
MH  - Rats, Wistar
MH  - Ryanodine Receptor Calcium Release Channel/*metabolism
MH  - Signal Transduction
MH  - Transforming Growth Factor beta/metabolism
OTO - NOTNLM
OT  - Chondrodysplasia
OT  - Endoplasmic reticulum stress
OT  - Prenatal dexamethasone exposure
OT  - Ryanodine receptor 1
OT  - Transforming growth factor beta
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2020/07/04 06:00
MHDA- 2020/12/15 06:00
CRDT- 2020/07/04 06:00
PHST- 2020/02/20 00:00 [received]
PHST- 2020/06/22 00:00 [revised]
PHST- 2020/06/26 00:00 [accepted]
PHST- 2020/07/04 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/07/04 06:00 [entrez]
AID - S0167-4889(20)30149-X [pii]
AID - 10.1016/j.bbamcr.2020.118791 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Cell Res. 2020 Oct;1867(10):118791. doi: 
      10.1016/j.bbamcr.2020.118791. Epub 2020 Jun 30.