TNF-α and IL-1β Promote a Disintegrin-like and Metalloprotease with Thrombospondin Type I Motif-5-mediated Aggrecan Degradation through Syndecan-4 in Intervertebral Disc
TNF-α and IL-1β Promote a Disintegrin-like and Metalloprotease with Thrombospondin Type I Motif-5-mediated Aggrecan Degradation through Syndecan-4 in Intervertebral Disc
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DOI：
10.1074/jbc.m111.264549
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发表时间：
2011-11-18
影响因子：
4.8
通讯作者：
Risbud, Makarand V.
中科院分区：
文献类型：
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作者：
Wang, Jianru;Markova, Dessislava;Risbud, Makarand V.
在椎间盘退变过程中观察到TNF-α、IL-1 β水平升高以及ADAMTS（一种具有血小板反应蛋白I型基序的去整合素样和金属蛋白酶）表达的增加。然而，这些促炎细胞因子是否控制ADAMTS活性尚不明确。该研究的目的是研究TNF-α和IL-1 β是否调节syndecan-4（SDC 4）表达，以及SDC 4是否负责通过控制椎间盘髓核细胞中ADAMTS活性来促进聚集蛋白聚糖降解。细胞因子处理增加SDC 4表达和启动子活性。使用抑制剂SM 7368和与I κ B α，RelA/p50共转染显示NF-κ B调节基础和烟碱依赖的SDC 4转录。携带RelA结合位点突变的SDC 4启动子对细胞因子无反应。此外，细胞因子未能增加SDC 4启动子在RelA无效细胞中的活性。细胞因子增加ADAMTS-4/5表达和聚集蛋白聚糖降解，并促进SDC 4与ADAMTS-5的相互作用。用肝素酶-III和对硝基苯基-β-D-吡喃木糖苷（PNPX）（硫酸乙酰肝素合成的抑制剂）处理和用SDC 4-shRNA转染部分阻断细胞因子介导的聚集蛋白聚糖降解。对人体组织的分析显示，随着椎间盘疾病的严重程度，聚集蛋白聚糖降解增加，同时SDC 4和ADAMTS-5蛋白表达增加。同样，SDC 4、TNF-α、IL-1 β、ADAMTS-4和ADAMTS-5 mRNA表达在退化组织中增加。我们的结论是，在髓核中，TNF-α和IL-1 β调节SDC 4的表达，这在退行性椎间盘疾病的发病机制中起着关键作用，通过促进ADAMTS-5的聚集蛋白聚糖降解。
Elevated levels of TNF-alpha, IL-1 beta and a resultant increase in ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type I motifs) expression is seen during disc degeneration. However, if these pro-inflammatory cytokines control ADAMTS activity is not definitively known. The goal of the investigation was to study if TNF-alpha and IL-1 beta regulate syndecan-4 (SDC4) expression, and if SDC4 was responsible for promoting aggrecan degradation through controlling ADAMTS activity in nucleus pulposus cells of the intervertebral disc. Cytokine treatment increased SDC4 expression and promoter activity. Use of inhibitor, SM7368 and co-transfections with I kappa B alpha, RelA/p50 showed that NF-kappa B regulated both basal and cytokine-dependent SDC4 transcription. SDC4 promoter har-boring RelA binding site mutation was unresponsive to the cytokines. Moreover, cytokines failed to increase SDC4 promoter activity in RelA-null cells. Cytokines increased ADAMTS-4/5 expression and aggrecan degradation and promoted SDC4 interaction with ADAMTS-5. Treatment with heparinase-III and p-nitrophenyl-beta-D-xylopyranoside (PNPX), an inhibitor of heparan sulfate synthesis and transfection with SDC4-shRNA partially blocked cytokine mediated aggrecan degradation. Analysis of human tissues showed increased aggrecan degradation with a concomitant increase in SDC4 and ADAMTS-5 protein expression with severity of disc disease. Likewise, SDC4, TNF-alpha, IL-1 beta, ADAMTS-4, and ADAMTS-5 mRNA expression increased in degenerate tissues. We conclude that in nucleus pulposus, TNF-alpha and IL-1 beta regulate SDC4 expression, which plays a key role in pathogenesis of degenerative disc disease by promoting aggrecan degradation by ADAMTS-5.