TiAl₆V₄ particles promote osteoclast formation via autophagy-mediated downregulation of interferon-beta in osteocytes

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• 作者：Zhenheng Wang^a ; ^b ; ¹ ; Zhantao Deng^a ; ¹ ; Jingjing Gan^a ; Gang Zhou^a ; Tongguo Shi^a ; Zhenzhen Wang^a ; Zhen Huang^a ; Hongbo Qian^a ; Nirong Bao^a ; Ting Guo^a ; Jiangning Chen^a ; Junfeng Zhang^a ; Feng Liu^a ; ^b ; ^{njliuf@163.com} ; Lei Dong^a ; ^{leidong@nju.edu.cn} ; Jianning Zhao^a ; ^{zhaojianning.0207@163.com}
• 关键词：Wear particles ; Osteoclastogenesis ; Nanotoxicity ; Osteocytes ; IFN-β
• 刊名：Acta Biomaterialia
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：48
• 期：Complete
• 页码：489-498
• 全文大小：2060 K
• 卷排序：48

文摘

Wear debris-induced osteolysis is the leading cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure in the medium and long term. Although osteocytes are the most abundant cells in bone and make direct contact with implants, the interaction between osteocytes and wear debris remains largely unknown. In the present study, we investigated the effect of TiAl6V4 alloy particles (TiPs) on osteocytes and the subsequent effects on osteoclast formation. Our study demonstrated that osteocyte-conditioned medium (CM) inhibited osteoclast differentiation from bone marrow monocytes (BMMs) to osteoclasts. However, TiPs attenuated this inhibitory effect. The expression of several osteoclastogenesis-associated factors, including receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), nitric oxide (NO) and interferon-beta (IFN-β), was examined, and we found that TiPs markedly decreased the expression of IFN-β, but not the other factors. In an osteoclastogenesis assay, our results suggested that the downregulation of IFN-β mediated the stimulatory effect of TiPs on osteoclastogenesis. Additional evidence suggested that TiPs decreased the expression of IFN-β in osteocytes via macroautophagy (hereinafter referred to as “autophagy”). Moreover, inhibiting autophagy with Atg5 siRNA prevented the increase in osteoclastogenesis induced by TiPs. Collectively, these results suggested a possible mechanism underlying wear debris-induced osteolysis.Statement of SignificanceFor the first time, our study demonstrated that Ti-alloy particles attenuated the inhibitory effect of osteocytes-conditioned medium on osteoclast formation. With an osteoclastogenesis assay, we found that the downregulation of IFN-β in osteocytes mediated the promoting effect of TiPs on osteoclast formation. Furthermore, our results suggested that TiPs-induced autophagy mediated the downregulation of IFN-β in osteocytes. Inhibition of autophagy recovered the expression of IFN-β and ameliorated the promoting effect of TiPs on osteoclast formation. Collectively, these findings suggest a possible mechanism underlying wear debris-induced osteolysis and identified autophagy inhibition in osteocytes as a potential therapeutic approach for wear debris induced osteolysis.