Original Research ARTICLE
Necrostatin-1 Attenuates Trauma-induced Mouse Osteoarthritis and IL-1β induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes
- 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.
Prof. wentao zhu, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, firstname.lastname@example.org
Prof. anmin chen, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, email@example.com