Title

Osteoclast Precursor Differentiation By Mcpip Via Oxidative Stress, Endoplasmic Reticulum Stress, And Autophagy

Keywords

ER stress; MCP-1; MCPIP; osteoclast differentiation; reactive oxygen species

Abstract

Osteoclasts (OCs) are responsible for bone resorption in inflammatory joint diseases. Monocyte chemotactic protein-1 (MCP-1) has been shown to induce differentiation of monocytes to OC precursors, but nothing is known about the underlying mechanisms. Here, we elucidate how MCPIP, induced by MCP-1, mediates this differentiation. Knockdown of MCPIP abolished MCP-1-mediated expression of OC markers, tartrate-resistant acid phosphatase, and serine protease cathepsin K. Expression of MCPIP induced p47 PHOX and its membrane translocation, reactive oxygen species formation, and induction of endoplasmic reticulum (ER) stress chaperones, up-regulation of autophagy marker, Beclin-1, and lipidation of LC3, and induction of OC markers. Inhibition of oxidative stress attenuated ER stress and autophagy, and suppressed expression of OC markers. Inhibition of ER stress by a specific inhibitor or by knockdown of IRE1 blocked autophagy and induction of OC markers. ER stress inducers, tunicamycin and thapsigargin, induced expression of OC markers. Autophagy inhibition by 3′-methyladenine, LY294002, wortmannin or by knockdown of Beclin-1 or Atg 7 inhibited MCPIP-induced expression of OC markers. These results strongly suggest that MCP-1-induced differentiation of OC precursor cells is mediated via MCPIP-induced oxidative stress that causes ER stress leading to autophagy, revealing a novel mechanistic insight into the role of MCP-1 in OCs differentiation. © The Author 2011.

Publication Date

12-1-2011

Publication Title

Journal of Molecular Cell Biology

Volume

3

Issue

6

Number of Pages

360-368

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1093/jmcb/mjr021

Socpus ID

83455245194 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/83455245194

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