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Proteasome inhibition suppress microgravity elevated RANK signaling during osteoclast differentiation.

Authors
  • Ethiraj, Purushoth1
  • Ottinger, Allie M1
  • Singh, Toolika1
  • Singh, Avinash2
  • Haire, Kayla M1
  • Reddy, Sakamuri V3
  • 1 Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
  • 2 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
  • 3 Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cytokine
Publisher
Elsevier
Publication Date
Aug 27, 2019
Volume
125
Pages
154821–154821
Identifiers
DOI: 10.1016/j.cyto.2019.154821
PMID: 31470364
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Microgravity (µXg) induces bone loss in astronauts during space missions. Therefore, it is necessary to delineate the underlying mechanisms which leads to bone loss for developing countermeasures. Osteoclasts (OCLs) are multinucleated cells, which resorb bone. Previously, we have demonstrated that simulated µXg enhances OCL formation. However, control of osteoclast bone resorption activity under μXg remains unclear. The OCL formation has been shown to be regulated by ubiquitin-proteasome pathway. Hence, we hypothesized that proteasome inhibition could regulate osteoclast differentiation under μXg. In this study, we identified that RAW264.7 preosteoclast cells treated with proteasome inhibitor (MG-132) suppress RANK receptor expression essential for OCL differentiation, but no effect on TRAF-6. We identified that MG-132 treatment abolished K48-linked poly-ubiquitination under μXg. Immunostaining confirms inhibition of protein ubiquitination and RANK expression in preosteoclast cells. Furthermore, proteasome inhibition suppresses the expression of SQSTM1/p62 under both the ground based Xg and μXg conditions. Also, confocal microscopy using Lyso-Tracker demonstrated that proteasomal inhibition suppress the co-localization of p62 and lysosomes. MG-132 inhibited RANKL induced proteasome activity. RAW264.7 cells treated with the proteasome inhibitor showed an increased level of p-c-Jun activity in control cultures, however decreased under µXg. In contrast, c-Fos and NFATc1 expression was decreased. In-addition, mouse bone marrow cultures treated with MG-132 suppress OCL formation and bone resorption activity. Thus, our findings suggest that proteasome inhibition represents a novel therapeutic approach for bone loss under µXg in space environment. Copyright © 2019 Elsevier Ltd. All rights reserved.

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