Cyclin-dependent kinase 9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines.
Cyclin-dependent kinase 9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines.
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DOI：
10.1002/art.38378
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发表时间：
2014-06
影响因子：
13.3
通讯作者：
Haudenschild, Dominik R.
中科院分区：
文献类型：
--
作者：
Yik, Jasper H. N.;Hu, Zi'ang;Kumari, Ratna;Christiansen, Blaine A.;Haudenschild, Dominik R.
CDK9控制原发性炎症反应基因的激活。我们确定CDK 9抑制是否可以保护软骨免受促炎细胞因子的分解代谢影响。在存在或不存在CDK9抑制剂Flavopiridol或siRNA的情况下，用不同的促炎刺激物（IL-1 β、脂多糖和TNF α）激发人软骨细胞。通过实时PCR测定炎症介质、分解代谢和合成代谢基因的mRNA表达。将软骨外植体与IL-1 β（有或没有Flavopiridol）孵育6天。通过释放糖胺聚糖（GAG）和裂解的II型胶原（Col2a）肽来评估软骨基质降解。通过Flavopiridol抑制CDK9或通过siRNA敲低，有效地抑制了所有三种促炎刺激物对iNOS mRNA的诱导。NF κ B-靶PCR阵列的结果显示，Flavopiridol抑制IL-1 β对广泛的炎症介质基因（67个测试基因中的59个）的诱导。CDK9抑制还抑制分解代谢基因MMP 1、3、9、13和ADAMTS4、5的诱导;但不影响合成代谢基因如Col2a、聚集蛋白聚糖和COMP以及管家基因的基础表达。通过葡萄糖-6-磷酸脱氢酶活性评估，Flavopiridol没有明显的短期细胞毒性。最后，在IL-1 β处理的软骨外植体中，Flavopiridol减少了基质降解产物GAG的释放和裂解的Col2a肽，但不影响长期软骨细胞活力。CDK9活性是软骨细胞中原发性炎症反应所必需的。Flavopiridol抑制炎症介质和分解代谢基因的诱导，以保护软骨免受促炎细胞因子的有害影响，而不影响细胞活力和功能。
CDK9 controls the activation of primary inflammatory response genes. We determined whether CDK9 inhibition protects cartilage from the catabolic effects of pro-inflammatory cytokines. Human chondrocytes were challenged with different pro-inflammatory stimuli (IL-1β, lipopolysaccharides, and TNFα), in the presence or absence of the CDK9 inhibitor Flavopiridol, or siRNA. The mRNA expression of inflammatory mediators, catabolic, and anabolic genes were determined by real-time PCR. Cartilage explants were incubated with IL-1β, with or without Flavopiridol, for 6 days. Cartilage matrix degradation was assessed by the release of glycosaminoglycan (GAG) and cleaved Type II collagen (Col2a) peptides. CDK9 inhibition by Flavopiridol, or knockdown by siRNA, effectively suppressed iNOS mRNA induction by all three pro-inflammatory stimuli. Results from NFkB-targets PCR array showed that Flavopiridol suppressed the induction of a broad range of inflammatory mediator genes (59 out of 67 tested) by IL-1β. CDK9 inhibition also suppressed induction of catabolic genes MMP 1, 3, 9, 13, and ADAMTS4, 5; but did not affect the basal expression of anabolic genes such as Col2a, aggrecan, and COMP, and housekeeping genes. Flavopiridol had no apparent short-term cytotoxicity as assessed by glucose-6-phosphate dehydrogenase activity. Finally, in IL-1β-treated cartilage explants, Flavopiridol reduced the release of matrix degradation products GAG and cleaved Col2a peptides, but did not affect long-term chondrocyte viability. CDK9 activity is required for the primary inflammatory response in chondrocytes. Flavopiridol suppresses the induction of inflammatory mediators and catabolic genes to protect cartilage from the deleterious effects of pro-inflammatory cytokines, without impacting cell viability and functions.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Ali S;Heathcote DA;Kroll SH;Jogalekar AS;Scheiper B;Patel H;Brackow J;Siwicka A;Fuchter MJ;Periyasamy M;Tolhurst RS;Kanneganti SK;Snyder JP;Liotta DC;Aboagye EO;Barrett AG;Coombes RC
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Coombes RC
影响因子：
27.4
作者：
Goldring MB;Otero M;Tsuchimochi K;Ijiri K;Li Y
通讯作者：
Li Y
影响因子：
4.9
作者：
Wang M;Sampson ER;Jin H;Li J;Ke QH;Im HJ;Chen D
通讯作者：
Chen D
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