title: Osteoclast precursor differentiation by MCPIP via oxidative stress, endoplasmic reticulum stress, and autophagy.
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.
authors: Burnett School of Biomedical Sciences,  College of Medicine, University of Central Florida, Orlando, FL 32816,  USA.
authors: Kangkai
authors: K
authors: Wang
authors: Jianli
authors: J
authors: Niu
authors: Hyunbae
authors: H
authors: Kim
authors: Pappachan E
authors: PE
authors: Kolattukudy
mesh_terms: D001343:Autophagy; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012260:Ribonucleases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D012260:Ribonucleases; C510646:ZC3H12A protein, human