Fu Yahui, Lei Jinlai, Zhuang Yan, Zhang Kun, Lu Daigang
Department of Orthopaedic Trauma, Xi'an Honghui Hospital, Xi'an Jiaotong University Health Science Center, Xi'an 710054, PR China.
Department of Orthopaedic Trauma, Xi'an Honghui Hospital, Xi'an Jiaotong University Health Science Center, Xi'an 710054, PR China.
Exp Cell Res. 2016 Nov 15;349(1):184-190. doi: 10.1016/j.yexcr.2016.10.014. Epub 2016 Oct 19.
The pro-inflammatory cytokine interleukin-1 beta (IL-1β) plays a crucial role in the pathogenesis of osteoarthritis (OA) by stimulating several mediators that contribute to cartilage degradation. The aim of this study was to investigate the effects and mechanism of high mobility group box 1 (HMGB1) inhibitors HMGB1 A-box on the expression of matrix metalloproteinase (MMP) and the production of inflammatory mediators in human osteoarthritis chondrocytes after activation by IL-1β. We found that the overexpression of HMGB1 A-box significantly decreased the IL-1β-stimulated the production of MMP-1, MMP-3 and MMP-9, and also reduced the elevated levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) associated with the inhibition of prostaglandin E2 (PGE2) and nitric oxide (NO) production in IL-1β-stimulated chondrocytes. In addition, overexpression of the HMGB1 A-box significantly inhibited the up-regulation of ADAMTS-4, ADAMTS-5 and HMGB1 caused by IL-1β in chondrocytes. Moreover, the overexpression of HMGB1 A-box markedly suppressed the IL-1β-mediated activation of the Toll-like receptor 4 (TRL4)/NF-κB pathway. Our observations indicated that the HMGB1 A-box can play a protective role by suppressing the IL-1β-induced expression of MMPs and that the production of inflammatory mediators in chondrocytes was associated with suppression of the HMGB1/TLR4/NF-κB pathway. In conclusion, HMGB1 A-box relieves the development of OA that may be associated with regulating the HMGB1/TLR4/NF-κB pathway.
促炎细胞因子白细胞介素-1β（IL-1β）通过刺激多种促成软骨降解的介质，在骨关节炎（OA）发病机制中起关键作用。本研究旨在探讨高迁移率族蛋白B1（HMGB1）抑制剂HMGB1 A盒对白细胞介素-1β激活后人骨关节炎软骨细胞中基质金属蛋白酶（MMP）表达及炎性介质产生的影响及机制。我们发现，HMGB1 A盒的过表达显著降低了IL-1β刺激的MMP-1、MMP-3和MMP-9的产生，还降低了诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的升高水平，这与抑制IL-1β刺激的软骨细胞中前列腺素E2（PGE2）和一氧化氮（NO）的产生有关。此外，HMGB1 A盒的过表达显著抑制了IL-1β诱导的软骨细胞中ADAMTS-4、ADAMTS-5和HMGB1的上调。而且，HMGB1 A盒的过表达显著抑制了IL-1β介导的Toll样受体4（TRL4）/核因子κB（NF-κB）途径的激活。我们的观察结果表明，HMGB1 A盒可通过抑制IL-1β诱导的MMPs表达发挥保护作用，软骨细胞中炎性介质的产生与HMGB1/TLR4/NF-κB途径的抑制有关。总之，HMGB1 A盒可缓解可能与调节HMGB1/TLR4/NF-κB途径相关的OA发展。
