T140阻断SDF-1/CXCR4信号通路并在骨关节炎疾病模型中防止软骨退化

为了探讨T140通过靶向阻断SDF-1/CXCR4信号通路调节体内关节软骨退变的作用,并为以后的临床研究提供一定的参考,将45只健康的Hartley豚鼠随机分成3组,分别为:T140处理组(n=15)、磷酸盐缓冲盐水对照组(n=15)和未处理对照组(n=15)。分别在处理的2周、6周、8周、10周和12周,通过酶联免疫吸附测定法定量血清中的SDF-1。在治疗12周时,收集膝关节胫骨的软骨用于HE和番红-O染色同时进行Mankin分级;使用RT-PCR测量基质金属蛋白酶(MMP-3,MMP-9和MMP-13),聚集蛋白聚糖(ACAN)和胶原蛋白Ⅱ(ColⅡ)的m RNA表达水平;通过蛋白质印迹测量ColⅡ蛋白的表达水平。T140组中的SDF-1含量升高。与对照相比,HE和番红-O染色显示T140处理的动物中的软骨损失较少。T140组软骨中MMP-3、MMP-9和MMP-13的mRNA表达水平明显低于其他组。而T140处理组软骨中ACAN和ColⅡ的mRNA表达水平明显升高,T140组和对照组中的ColⅡ蛋白水平各不相同。T140可以通过在体内阻断SDF-1/CRCR4信号传导途径来下调基质金属酶的表达水平并减轻软骨的变性,为治疗OA的药理学提供了靶标。

T140 Blocks the SDF-1/CXCR4 Signaling Pathway and Prevents Cartilage Degradation in Osteoarthritis Models

To investigate the role of T140 in regulating the degeneration of articular cartilage in vivo by targeting the SDF-1/CXCR4 signaling pathway and providing a reference for future clinical studies.Forty-five healthy Hartley guinea pigs were randomized into three groups,T140 treatment group(n=15),phosphate buffered saline control group(n=15),and untreated control group(n=15).Serum SDF-1 was quantified by enzyme-linked immunosorbent assay at 2,6,8,10 and 12 weeks of treatment,respectively.At 12 weeks of treatment,cartilage of the knee tibia was collected for HandE and Safranin-O staining while Mankin fractionation;matrix metalloproteinases(MMP-3,MMP-9 and MMP-13)were measured by RT-PCR,and aggregated proteins were collected.mRNA expression levels of glycans(ACAN)and collagenⅡ(ColⅡ);expression levels of ColⅡprotein were measured by Western blotting.The content of SDF-1 in the T140 group increased.HandE and Safranin-O staining showed less cartilage loss in T140 treated animals compared to controls.The mRNA expression levels of MMP-3,MMP-9 and MMP-13 in the T140 group were significantly lower than those in the other groups.The mRNA expression levels of ACAN and ColⅡin the cartilage of T140 treatment group were significantly increased,and the levels of ColⅡprotein in T140 group and control group were different.T140 can down-regulate the expression level of matrix metalloenzyme and reduce the degeneration of cartilage by blocking the SDF-1/CRCR4 signaling pathway in vivo,providing a target for providing pharmacology for the treatment of OA.