Research Papers: Gerotarget (Focus on Aging):
Glucocorticoid impairs cell-cell communication by autophagy-mediated degradation of connexin 43 in osteocytes
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Junjie Gao1,*, Tak Sum Cheng1,*, An Qin2, Nathan J. Pavlos1, Tao Wang1,3, Kai Song1, Yan Wang4, Lianzhi Chen1, Lin Zhou4, Qing Jiang5, Hiroshi Takayanagi1,6, Sheng Yan7,4 and Minghao Zheng7,4,1
1 Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Nedlands, Western Australia, Australia
2 Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3 Division of Orthopaedic Surgery, Department of Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
4 Key Laboratory of Combined Muti-organ Transplantation, Ministry of Public Health, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
5 Department of Sports Medicine and Adult Reconstruction Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, Jiangsu, China
6 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
7 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
* These authors have contributed equally to this work
Minghao Zheng, email:
Sheng Yan, email:
Keywords: osteocyte; connexin 43; autophagy; glucocorticoid; mTORC1; Gerotarget
Received: March 03, 2016 Accepted: April 08, 2016 Published: April 27, 2016
Osteocytes comprising over 90% of the bone cell population are highly susceptible to the adverse effects of glucocorticoids (GC) administration. Here we observed that Dexamethasone (Dex) induces a robust cytoskeleton rearrangement and decreases Cx43 protein expression in osteocyte-like MLO-Y4 cells. Using a Dmp1Cre-mT/mG osteocyte ex vivo culture system, we found significant shortening of dendritic processes in primary osteocytes following Dex administration. Loss of dendritic processes is a consequence of reduced Cx43 connectivity upon Dex induced autophagy in both RFP-GFP-LC3B transfected MLO-Y4 cells and primary calvarial osteocytes from LC3GFP transgenic mice. Upon the induction of autophagy by Dex, Cx43 was internalized into autophagosome/autolysosomes and degraded by autophagy. The degradation was attenuated following lysosomal inhibition using chloroquine (CLQ) and suppression of autophagy by Atg5 silencing. Inhibition Akt-mTORC1 signaling by Dex induces autophagy subsequently resulting in Cx43 degradation.Activation of Akt phosphorylation by IGF-1 attenuated Dex induced autophagy and degradation of Cx43. Together, we demonstrated that GC impair osteocyte cell-cell connectivity via autophagy mediated degradation of Cx43 through inhibition of the Akt-mTORC1 signaling. This may account for the deleterious effect of GC-induced bone loss.
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