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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01378

Necrostatin-1 Attenuates Trauma-induced Mouse Osteoarthritis and IL-1β induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes

 Shuang Liang1,  Zhengtao Lv1, 2,  jiaming zhang1, yuting wang1, yonghui dong3, zhenggang wang1,  Kun Chen1, 2,  peng cheng1,  qing yang1,  Fengjing Guo1, weiwei lu1, wentao zhu1* and anmin chen1*
  • 1Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
  • 2Harvard School of Dental Medicine, United States
  • 3Henan Provincial People's Hospital, China

Necrostatin-1 (Nec-1) is a specific small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1) that specifically inhibitinhibits phosphorylation of RIPK1. RIPK1 regulates inflammation and cell death by interacting with receptor-interacting serine/threonine protein kinases 3(RIPK3). We hypothesised that Nec-1 may have anti-inflammatory efficacy in patients with osteoarthritis (OA), as the pathophysiology of OA involves the activation of inflammation-related signalling pathways and apoptosis. In this study, we explored the effects of Nec-1 on interleukin (IL)-1β-induced inflammation in mouse chondrocytes and the destabilised medial meniscus (DMM) mouse model. Inhibiting RIPK1 with Nec-1 dramatically suppressed catabolism both in vivo and in vitro, but did not inhibit changes in subchondral bone. Nec-1 abolished the in vitro increases in matrix metalloproteinase and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTs5) expression induced by IL-1β. However, adding high-mobility group box 1 (HMGB1) partially abrogated this effect, indicating the essential role of HMGB1 and Nec-1 in the protection of primary chondrocytes. Furthermore, Nec-1 decreased the expression of Toll-like receptor 4 (TLR4) and stromal cell-derived factor-1 (SDF-1), and attenuated the interaction between TLR4 and HMGB1. Western blot results suggested that Nec-1 significantly suppressed IL-1β-induced NF-𝜅B transcriptional activity, but not pathway. Micro-computed tomography, immunohistochemical staining, and Safranin O/Fast Green staining were used in vivo to assess the degree of destruction of OA cartilage, and the results were consistent with the in vitro experiments. Therefore, Nec-1 may be a novel therapeutic candidate to treat OA.

Keywords: necrostatin-1, Osteoarthristis, chondrocyte, necroptosis, Apoptosis, Inflammation

Received: 15 Aug 2018; Accepted: 09 Nov 2018.

Edited by:

Per-Johan Jakobsson, Karolinska Institutet (KI), Sweden

Reviewed by:

Marina Korotkova, Karolinska Institutet (KI), Sweden
Soon Yew Tang, University of Pennsylvania, United States  

Copyright: © 2018 Liang, Lv, zhang, wang, dong, wang, Chen, cheng, yang, Guo, lu, zhu and chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. wentao zhu, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, wentao-zhu@hotmail.com
Prof. anmin chen, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, anminchen@hust.edu.cn