Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines.
Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines.
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DOI：
10.1186/ar3456
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发表时间：
2011
影响因子：
4.9
通讯作者：
Grodzinsky AJ
中科院分区：
文献类型：
--
作者：
Lu YC;Evans CH;Grodzinsky AJ
创伤性关节损伤损害软骨，导致邻近关节组织释放炎性细胞因子，增加发生骨关节炎的风险。本研究的主要目的是确定短期应用糖皮质激素如地塞米松能否消除机械损伤、肿瘤坏死因子α和白介素6/可溶性白介素6R对软骨的联合分解作用。在最初的地塞米松剂量反应研究中，用肿瘤坏死因子α和增加浓度的地塞米松处理牛软骨移植。分别用肿瘤坏死因子α、IL-6/sIL-6R和地塞米松或地塞米松联合处理牛和人软骨组织。通过检测糖胺多聚糖(GAG)向培养液中的释放和蛋白多糖的合成来评估治疗效果。其他实验测试了预先将软骨暴露于地塞米松是否可以防止细胞因子引起的GAG丢失和生物合成抑制，以及地塞米松的后处理是否可以减弱预先确定的细胞因子损伤的影响。检测损伤、肿瘤坏死因子α和地塞米松联合作用下软骨内稳相关基因(蛋白酶、基质分子、细胞因子、生长因子和转录因子)的信使核糖核酸水平。为探讨地塞米松调节软骨细胞代谢反应的机制，应用糖皮质激素受体(GR)拮抗剂(RU486)和蛋白原转换酶抑制剂(RVKR-CMK)。地塞米松剂量依赖性地抑制肿瘤坏死因子α引起的GAG丢失和生物合成减少。机械损伤、肿瘤坏死因子α和IL-6/sIL-6R的共同作用导致最严重的GAG丢失；地塞米松将这种GAG丢失减少到控制牛和人软骨的水平。此外，地塞米松对牛外植体的前处理或后处理降低了暴露于肿瘤坏死因子α的软骨外植体的GAG损失，并增加了蛋白多糖的合成。地塞米松不能下调血管紧张素转换酶基因的表达。地塞米松对与损伤和细胞因子反应相关的其他基因的转录后调控也被注意到。GR拮抗剂逆转地塞米松对硫酸盐掺入的影响。RVKR-CMK可显著减少肿瘤坏死因子α+IL-6+损伤所致的GAG丢失。短期糖皮质激素治疗有效地消除了促炎细胞因子和机械损伤相结合的分解代谢效应：地塞米松阻止了蛋白多糖的降解和恢复了生物合成。地塞米松似乎在转录后调节软骨细胞的分解代谢反应，因为在地塞米松存在的情况下，编码聚集聚糖酶的转录本的丰度仍然增加。
Traumatic joint injury damages cartilage and causes adjacent joint tissues to release inflammatory cytokines, increasing the risk of developing osteoarthritis. The main objective of this study was to determine whether the combined catabolic effects of mechanical injury, tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)/soluble IL-6 receptor (sIL-6R) on cartilage could be abolished by short-term treatment with glucocorticoids such as dexamethasone. In an initial dexamethasone-dose-response study, bovine cartilage explants were treated with TNFα and increasing concentrations of dexamethasone. Bovine and human cartilage explants were then subjected to individual and combined treatments with TNFα, IL-6/sIL-6R and injury in the presence or absence of dexamethasone. Treatment effects were assessed by measuring glycosaminoglycans (GAG) release to the medium and synthesis of proteoglycans. Additional experiments tested whether pre-exposure of cartilage to dexamethasone could prevent GAG loss and inhibition of biosynthesis induced by cytokines, and whether post-treatment with dexamethasone could diminish the effects of pre-established cytokine insult. Messenger ribonucleic acid (mRNA) levels for genes involved in cartilage homeostasis (proteases, matrix molecules, cytokines, growth and transcription factors) were measured in explants subjected to combined treatments with injury, TNFα and dexamethasone. To investigate mechanisms associated with dexamethasone regulation of chondrocyte metabolic response, glucocorticoid receptor (GR) antagonist (RU486) and proprotein convertase inhibitor (RVKR-CMK) were used. Dexamethasone dose-dependently inhibited GAG loss and the reduction in biosynthesis caused by TNFα. The combination of mechanical injury, TNFα and IL-6/sIL-6R caused the most severe GAG loss; dexamethasone reduced this GAG loss to control levels in bovine and human cartilage. Additionally, dexamethasone pre-treatment or post-treatment of bovine explants lowered GAG loss and increased proteoglycan synthesis in cartilage explants exposed to TNFα. Dexamethasone did not down-regulate aggrecanase mRNA levels. Post-transcriptional regulation by dexamethasone of other genes associated with responses to injury and cytokines was noted. GR antagonist reversed the effect of dexamethasone on sulfate incorporation. RVKR-CMK significantly reduced GAG loss caused by TNFα + IL-6 + injury. Short-term glucocorticoid treatment effectively abolished the catabolic effects exerted by the combination of pro-inflammatory cytokines and mechanical injury: dexamethasone prevented proteoglycan degradation and restored biosynthesis. Dexamethasone appears to regulate the catabolic response of chondrocytes post-transcriptionally, since the abundance of transcripts encoding aggrecanases was still elevated in the presence of dexamethasone.
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影响因子：
4.8
作者：
Fitzgerald, JB;Jin, M;Grodzinsky, AJ
通讯作者：
Grodzinsky, AJ
影响因子：
--
作者：
DiMicco, MA;Patwari, P;Grodzinsky, AJ
通讯作者：
Grodzinsky, AJ
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
影响因子：
158.5
作者：
Frobell, Richard B.;Roos, Ewa M.;Lohmander, L. Stefan
通讯作者：
Lohmander, L. Stefan
影响因子：
5.1
作者：
Creamer, P
通讯作者：
Creamer, P