Growth differentiation factor-6 attenuates inflammatory and pain-related factors and degenerated disc-induced pain behaviors in rat model
Growth differentiation factor-6 attenuates inflammatory and pain-related factors and degenerated disc-induced pain behaviors in rat model
复制标题
生长分化因子 6 减轻大鼠模型中炎症和疼痛相关因素以及椎间盘退化引起的疼痛行为
DOI：
10.1002/jor.24793
复制
发表时间：
2020-09-14
影响因子：
2.8
通讯作者：
Zheng, Zhaomin
中科院分区：
文献类型：
--
作者：
Cui, Haowen;Zhang, Jian;Zheng, Zhaomin
以往的研究表明，生长分化因子6(GDF6)是治疗椎间盘退行性变(IDD)的潜在候选因子。在这里，我们通过检测椎间盘结构的变化以及炎症和疼痛相关因子的表达来研究GDF6对IDD的影响。建立单节段、连续3个节段的大鼠后路椎间盘穿刺术模型，术后1周或2周分别给予GDF6或磷酸盐缓冲液。磁共振成像显示穿刺区有明显的退变信号，GDF6对其有抑制作用。组织学染色显示，GDF6对大鼠穿刺术后8周的IVD结构无明显改善作用，但对IVD中肿瘤坏死因子-α(TNF-α)和白介素1β(IL-1β)的表达有抑制作用。此外，GDF6对术后32周的IVD的形态和结构也有保护作用。机械性和热敏性痛觉过敏实验表明，GDF6可明显改善机械刺激和热刺激大鼠的痛觉行为，抑制脊神经节炎症因子TNF-α、IL-1β和疼痛因子降钙素基因相关肽的表达。大鼠蛋白质芯片实验表明，GDF6可降低肿瘤坏死因子诱导的IDD细胞模型中细胞因子IL-6、细胞间黏附分子-1、基质金属蛋白酶-13、IL-1β和肿瘤坏死因子-α的表达，上调金属蛋白酶组织抑制因子1、转化生长因子-β2、IL-10和抵抗素的表达。因此，我们的研究表明GDF6可以改善IVD的结构，抑制炎症和疼痛相关因子的表达，改善大鼠的疼痛行为。临床意义：为了建立进一步的临床前研究和临床试验，需要全面的数据来验证GDF6的再生特性。理想情况下，再生剂也应该能够缓解间盘源性疼痛，达到最佳的临床结果。
Previous studies have indicated that growth differentiation factor 6 (GDF6) is a potential candidate for intervertebral disc (IVD) degeneration (IDD) treatment. Here, we investigated the effect of GDF6 on IDD by examining changes in disc structure and the expression of inflammatory and pain-related factors. A rat posterior disc puncture model of single segments and three consecutive segments was constructed, and GDF6 or phosphate-buffered solution was administered via intradiscal injection 1 or 2 weeks after surgery. Magnetic resonance imaging showed a clear degeneration signal in the punctured disc, which was inhibited by GDF6. Histological staining revealed that GDF6 did not significantly improve the structure of IVDs in rats 8 weeks after puncture surgery, but it had an inhibitory effect on expression of the tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1 beta in the IVD. Furthermore, GDF6 was found to protect the morphology and structure of the IVD 32 weeks after surgery. Mechanical and thermal hyperalgesia tests suggested that GDF6 injection can significantly improve mechanical and thermal-stimulated pain behavior in rats and inhibit the expression of inflammatory factors TNF-alpha and IL-1 beta and the pain factor calcitonin gene-related peptide in the dorsal root ganglion. A rat protein array test indicated that GDF6 could reduce the expression of cytokines IL-6, intercellular cell adhesion molecule-1, matrix metalloproteinase-13, IL-1 beta, and TNF-alpha and increase the expression of tissue inhibitor of metalloproteinases 1, Transforming growth factor-beta 2, IL-10, and resistin in a TNF-alpha-induced IDD cell model. Thus, our study demonstrates that GDF6 can improve the structure of the IVD, inhibit the expression of inflammatory and pain-related factors, and improve pain behavior in rats. Clinical Significance: To establish further preclinical research and clinical trials, comprehensive data are needed to validate the regenerative properties of GDF6. Ideally, a regenerative agent should also be able to relieve discogenic pain, achieving the best clinical outcomes.