Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis
Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis
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DOI：
10.1111/jphp.12379
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发表时间：
2015-07-01
影响因子：
3.3
通讯作者：
Hu, Xiang-yang
中科院分区：
文献类型：
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作者：
Li, Rong;Cai, Li;Hu, Xiang-yang
目的研究环巴胺抑制Hedgehog（Hh）信号是否能减轻佐剂性关节炎（AIA）大鼠的炎症和软骨损伤。方法在AIA诱导后第12 ~ 21天，每天腹腔注射环巴胺（2.5、5、10 mg/kg）。爪肿胀（体积变化）、血清促炎细胞因子水平（ELISA）、关节损伤的组织学分析（H&E染色），蛋白聚糖表达（阿辛蓝染色），声波Hh（Shh），神经胶质瘤相关癌基因同源物1（Gli 1），软骨中的II型胶原（COII）和聚集蛋白聚糖（实时PCR）和关节软骨细胞凋亡（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）主要发现环巴胺可有效减轻AIA大鼠的炎症和软骨损伤，表现为足爪肿胀减轻、血清肿瘤坏死因子（TNF）-、IL-1、IL-6和关节损伤的组织学评分，关节软骨中COII和聚集蛋白聚糖的蛋白聚糖表达和mRNA水平增加。Shh或Gli 1 mRNA水平与COII和聚集蛋白聚糖mRNA水平呈负相关，表明Hh信号抑制与促进软骨细胞外基质的产生有关。此外，cyclopamine减少AIA大鼠的关节软骨细胞凋亡的数量，这可能是部分相关的机制，减轻软骨damage.ConclusionsOur研究结果提出了一些实验证据，Hh信号抑制可能是潜在的临床兴趣，在类风湿关节炎的治疗。
ObjectivesWe investigated whether inhibition of hedgehog (Hh) signal by cyclopamine attenuated inflammation and cartilage damage in adjuvant-induced arthritis (AIA) rats.MethodsCyclopamine (2.5, 5, 10mg/kg) was given by intraperitoneal injection once daily from day 12 to 21 after AIA induction. Paw swelling (volume changes), serum pro-inflammatory cytokines levels (ELISA), histological analysis of joint damage (H&E staining), proteoglycans expression (Alcian blue staining), mRNA levels of sonic Hh (Shh), glioma-associated oncogene homologue 1 (Gli1), type II collagen (COII) and aggrecan in cartilage (real-time PCR) and articular chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) were measured respectively.Key findingsCyclopamine effectively attenuated inflammation and cartilage damage of AIA rats, as evidenced by reduced paw swelling, serum levels of tumor necrosis factors (TNF)-, IL-1, IL-6 and histological scores of joint damage, increased proteoglycans expression and mRNA levels of COII and aggrecan in articular cartilage. Shh or Gli1 mRNA level was correlated negatively with COII and aggrecan mRNA levels, suggesting Hh signal inhibition was associated with promotion of cartilage extracellular matrix production. Furthermore, cyclopamine decreased the number of apoptotic articular chondrocytes of AIA rats, which might be partly related to its mechanisms on relieving cartilage damage.ConclusionsOur findings present some experimental evidence that Hh signal inhibition might be of potential clinical interest in rheumatoid arthritis treatment.