Glucocorticoid impairs cell-cell communication by autophagymediated degradation of connexin 43 in osteocytes

Junjie Gao, Tak Sum Cheng, A. Qin, Nathan Pavlos, Tao Wang, Kai Song, Y. Wang, Lianzhi Chen, L. Zhou, Q. Jiang, Hiroshi Takayanagi, S. Yan, Minghao Zheng

    Research output: Contribution to journalArticle

    36 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)26966-26978
    JournalOncotarget
    Volume7
    Issue number19
    Early online date27 Apr 2016
    DOIs
    Publication statusPublished - 10 May 2016

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