Crucial role of the terminal complement complex in chondrocyte death and hypertrophy after cartilage trauma
Crucial role of the terminal complement complex in chondrocyte death and hypertrophy after cartilage trauma
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DOI：
10.1016/j.joca.2020.01.004
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发表时间：
2020-05-01
影响因子：
7
通讯作者：
Brenner, R. E.
中科院分区：
文献类型：
--
作者：
Riegger, J.;Huber-Lang, M.;Brenner, R. E.
目的：先天性免疫反应，特别是终末补体复合物（TCC）沉积被认为参与创伤后骨关节炎的发病机制。然而，TCC在调节性细胞死亡以及软骨细胞肥大和衰老中的可能作用迄今尚未阐明，并且首次使用离体人软骨创伤模型来解决。（0.59 J）并暴露于人血清（HS）和软骨匀浆（HG），有或没有不同的潜在治疗剂：RIPK 1抑制剂Necrostatin-1（Nec）、半胱天冬酶抑制剂zVAD、抗氧化剂N-乙酰半胱氨酸（NAC）和TCC抑制剂金精三羧酸（ATA）和丛生蛋白（CLU）。细胞死亡和肥大/衰老相关的标志物进行了评估的mRNA和蛋白质level.Results：此外HS导致显着增强TCC软骨细胞上的沉积和减少创伤后的细胞活力。HG可增强这种作用，并与RIPK 3、MLKL和CASP 8的表达相关。HS的细胞毒性可以通过热灭活或特异性抑制剂来防止，其中Nec和zVAD以及ATA的组合表现出最高的细胞保护。此外，HS+HG曝光增强CXCL 1，IL-8，RUNX 2和VEGFA的基因表达以及分泌IL-6后软骨traum.Conclusions：我们的研究结果意味着至关重要的参与补体系统，主要是TCC在调节细胞死亡和表型变化后软骨细胞的软骨traum. Conclusions。抑制TCC形成或下游信号传导在很大程度上改变了血清诱导的病理生理效应，因此可能代表了维持软骨细胞存活和软骨形成特性的治疗靶点。(C)2020年国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Innate immune response and particularly terminal complement complex (TCC) deposition are thought to be involved in the pathogenesis of posttraumatic osteoarthritis. However, the possible role of TCC in regulated cell death as well as chondrocyte hypertrophy and senescence has not been unraveled so far and was first addressed using an ex vivo human cartilage trauma-model.Design: Cartilage explants were subjected to blunt impact (0.59 J) and exposed to human serum (HS) and cartilage homogenate (HG) with or without different potential therapeutics: RIPK1-inhibitor Necrostatin-1 (Nec), caspase-inhibitor zVAD, antioxidant N-acetyl cysteine (NAC) and TCC-inhibitors aurin-tricarboxylic acid (ATA) and clusterin (CLU). Cell death and hypertrophy/senescence-associated markers were evaluated on mRNA and protein level.Results: Addition of HS resulted in significantly enhanced TCC deposition on chondrocytes and decrease of cell viability after trauma. This effect was potentiated by HG and was associated with expression of RIPK3, MLKL and CASP8. Cytotoxicity of HS could be prevented by heat-inactivation or specific inhibitors, whereby combination of Nec and zVAD as well as ATA exhibited highest cell protection. Moreover, HS+HG exposition enhanced the gene expression of CXCL1, IL-8, RUNX2 and VEGFA as well as secretion of IL-6 after cartilage trauma.Conclusions: Our findings imply crucial involvement of the complement system and primarily TCC in regulated cell death and phenotypic changes of chondrocytes after cartilage trauma. Inhibition of TCC formation or downstream signaling largely modified serum-induced pathophysiologic effects and might therefore represent a therapeutic target to maintain the survival and chondrogenic character of cartilage cells. (C) 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.