Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection.
Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection.
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DOI：
10.1002/art.33444
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发表时间：
2012-04
影响因子：
--
通讯作者：
Lotz, Martin
中科院分区：
文献类型：
--
作者：
Carames, Beatriz;Taniguchi, Noboru;Seino, Daisuke;Blanco, Francisco J.;D'Lima, Darryl;Lotz, Martin
机械损伤导致软骨细胞死亡，并触发重塑过程，最终表现为骨关节炎(OA)。自噬是细胞内细胞器和大分子的周转过程，在应激反应中保护细胞。本研究确定了软骨机械损伤后自噬的变化和功能。对牛和人软骨移植块进行机械冲击(40%应变，500ms)。观察细胞存活率、硫酸糖胺聚糖(SGAG)释放及自噬标志物ULK1、Beclin1和LC3的变化。用mTORC1I抑制剂和自噬诱导剂雷帕霉素处理软骨组织，检测其对机械损伤、细胞死亡诱导剂一氧化氮和肿瘤坏死因子α+放线菌素D以及促炎细胞因子IL-1α的保护作用。机械损伤以时间依赖的方式诱导SGAG细胞死亡和丢失。这与损伤后48小时软骨浅层ULK1、Beclin1和Lc3的表达显著降低有关(P<；0.05)。LC_3-II水平在伤后24小时升高，48小时和96小时下降。在机械损伤的外植体中，雷帕霉素增强自噬调节因子的表达，防止细胞死亡和SGAG丢失。雷帕霉素对硝普钠、肿瘤坏死因子α+放线菌素D诱导的细胞死亡有保护作用，对IL-1α诱导的SGAG丢失有保护作用。机械损伤导致自噬的抑制，主要发生在细胞死亡最多的浅表区域。对mTORC1的药理抑制，至少部分是通过增强自噬来防止细胞和基质的损伤，这表明了一种新的软骨保护方法。
Mechanical injury induces cell death in cartilage and triggers a remodeling process that ultimately can manifest as osteoarthritis (OA). Autophagy is a process for turnover of intracellular organelles and macromolecules that protects cells during stress responses. This study determined changes and functions of autophagy following mechanical injury to cartilage. Bovine and human cartilage explants were subjected to mechanical impact (40% strain, 500 ms). Cell viability, sulfated glycosaminoglyan (sGAG) release and changes in autophagy markers ULK1, Beclin1 and LC3 were evaluated. Cartilage explants were also treated with the mTORC1 inhibitor and autophagy inducer rapamycin and tested for protective effects against mechanical injury, the cell death inducers nitric oxide and TNFα+Actinomycin D and the proinflammatory cytokine IL-1α. Mechanical injury induced cell death and loss of sGAG in a time-dependent manner. This was associated with significantly decreased ULK1, Beclin1 and LC3 expression in the cartilage superficial zone (P < 0.05) at 48 hours post-injury. The levels of LC3-II were increased at 24 hours post-injury but decreased at 48 and 96 hours. Rapamycin enhanced expression of autophagy regulators and prevented cell death and sGAG loss in mechanically injured explants. Rapamycin also protected against cell death induced by SNP, TNFα+Actinomycin D and prevented sGAG loss induced by IL-1α. Mechanical injury leads to suppression of autophagy, predominantly in the superficial zone where most of the cell death occurs. Pharmacological inhibition of mTORC1, at least in part by enhancement of autophagy prevented cell and matrix damage suggesting a novel approach for chondroprotection.
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影响因子：
7.3
作者：
Grogan, SP;Aklin, B;Mainil-Varlet, P
通讯作者：
Mainil-Varlet, P
影响因子：
37.8
作者：
Inuzuka, Yasutaka;Okuda, Junji;Shioi, Tetsuo
通讯作者：
Shioi, Tetsuo
影响因子：
13.3
作者：
Furuya, Norihiko;Yu, Jie;Levine, Beth
通讯作者：
Levine, Beth
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
DOI：
10.1016/0304-4165(86)90306-5
发表时间：
1986-09-04
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
FARNDALE, RW;BUTTLE, DJ;BARRETT, AJ
通讯作者：
BARRETT, AJ