Wang Kun, Li Yanlin, Han Rui, Cai Guofeng, He Chuan, Wang Guoliang, Jia Di
Department of Sports Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Department of Diabetology, First Affiliated Hospital of Kunming Medical University, Kunming, China.
PLoS One. 2017 Apr 20;12(4):e0176048. doi: 10.1371/journal.pone.0176048. eCollection 2017.
Osteoarthritis (OA) is one of the most common diseases affecting older people; however, there remains no effective targeted drug to combat OA. The aims of this study were (1) to explore the effect of T140 in regulating degeneration of articular cartilage in vivo by targeted blocking of the SDF-1/CXCR4 signaling pathway, and (2) to provide experimental evidence for the development of a novel OA-targeted pharmacotherapy. Thirty-six healthy Hartley guinea pigs were randomly divided into three groups: a T140-treated group (n = 12), a phosphate buffer saline control group (n = 12) and an untreated control group (n = 12). At 2, 4, 6, 8, 10 and 12 weeks of treatment, SDF-1 in serum was quantified by enzyme-linked immunosorbent assay. At 12 weeks of treatment, the cartilage from knee tibial plateau in the knee joint was collected for H&E, Safranin-O staining and Mankin grading; measurement for mRNA levels of matrix metalloproteinases (MMP-3, MMP-9 and MMP-13), aggrecan (ACAN) and collagen II (Col II) using RT-PCR; and measurement for Col II protein levels by western blot. Results showed that SDF-1 in serum increased in the T140 group and increased in the control groups. H&E and Safranin-O staining revealed less cartilage loss in T140-treated animals compared to controls. The mRNA levels of MMP-3, MMP-9 and MMP-13 in cartilage were much lower in the T140 group than other groups, but mRNA levels of ACAN and Col II in cartilage were higher in the T140-treated group. Col II protein levels in the T140 group and control groups were different. T140 can downregulate the expression of matrix-degrading enzyme and lessen the degeneration of cartilage by blocking the SDF-1/CRCR4 signaling pathway in vivo. This mechanism may present a pharmacological target for the treatment of OA.
骨关节炎（OA）是影响老年人的最常见疾病之一；然而，目前仍没有有效的靶向药物来对抗OA。本研究的目的是：（1）通过靶向阻断SDF-1/CXCR4信号通路，探索T140在体内调节关节软骨退变的作用；（2）为开发新型OA靶向药物治疗提供实验证据。将36只健康的Hartley豚鼠随机分为三组：T140治疗组（n = 12）、磷酸盐缓冲盐水对照组（n = 12）和未治疗对照组（n = 12）。在治疗的第2、4、6、8、10和12周，采用酶联免疫吸附测定法对血清中的SDF-1进行定量。在治疗12周时，收集膝关节胫骨平台的软骨进行苏木精-伊红（H&E）染色、番红O染色和曼金评分；采用逆转录-聚合酶链反应（RT-PCR）检测基质金属蛋白酶（MMP-3、MMP-9和MMP-13）、聚集蛋白聚糖（ACAN）和胶原蛋白II（Col II）的mRNA水平；通过蛋白质免疫印迹法检测Col II蛋白水平。结果显示，T140组血清中的SDF-1增加，对照组也增加。H&E染色和番红O染色显示，与对照组相比，T140治疗的动物软骨损失较少。T140组软骨中MMP-3、MMP-9和MMP-13的mRNA水平远低于其他组，但T140治疗组软骨中ACAN和Col II的mRNA水平较高。T140组和对照组的Col II蛋白水平不同。T140可通过在体内阻断SDF-1/CRCR4信号通路来下调基质降解酶的表达，减轻软骨退变。这一机制可能为OA的治疗提供一个药理学靶点。
