Protective effect of P188 in the Model of Acute Trauma to Human Ankle Cartilage: The Mechanism of Action
Protective effect of P188 in the Model of Acute Trauma to Human Ankle Cartilage: The Mechanism of Action
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DOI：
10.1097/bot.0b013e3181ec4712
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发表时间：
2010-09-01
影响因子：
2.3
通讯作者：
Chubinskaya, Susan
中科院分区：
文献类型：
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作者：
Bajaj, Sarvottam;Shoemaker, Thomas;Chubinskaya, Susan
目的：由于P188波洛沙姆对急性创伤模型的细胞存活有促进作用。目的是了解其作用机制，重点是糖原合成酶激酶-3 （GSK3）的激活。白细胞介素- 6 (il - 6)。设计：使用直径为4毫米、脉冲为1毫微米的压头撞击16个正常人的tali。去除4毫米的影响核心和4毫米相邻的非影响环，用P188或不含P188培养细胞裂解物，使用Western blots检测总和磷酸化细胞外信号调节蛋白激酶（ERK）、c-Jun NH(2)末端激酶（INK）、p38、ATF-2、GSK3、Stall和Stat3的抗体。所研究的途径在撞击后被激活，P188在1小时达到活性峰值，完全减弱了Statl和ATF-2的磷酸化，抑制了p38、Stat3。物。p38i部分抵消Stat3的磷酸化。GSK3和ERK表明p38在这三种途径中发挥作用。此外，p38i改善了细胞存活（P = 0.053）并减少了细胞凋亡（约20%）。结论：我们的研究结果报告了P188在急性损伤模型中发挥其对软骨保护作用的新机制1，除了对细胞膜的作用外，p88还影响应激相关的1)38信号，凋亡相关的GSK3和炎症相关的IL-6信号。这些发现表明，P188单独使用或与proanabohc联合使用可能在预防进行性软骨变性和创伤后骨关节炎的发展方面具有治疗潜力
Objective: Because P188 poloxamer is effective in promoting cell survival in models of acute trauma. the objectives wet e to understand the mechanism of its action focusing on glycogen synthase kinase-3 (GSK3) activation. interleukin-6 (IL-6). and p38 signalingDesign: Sixteen normal human tali were impacted using a 4-mm diameter indenter with an impulse of 1 Ns Eight-millimeter cartilage plugs containing. the 4-mm impacted core and 4-mm adjacent nonimpacted ring were removed and cultured with, or without P188 Cell lysates were analyzed using Western blots with antibodies against total and phosphorylated extracellular signal-regulated protein kine (ERK), c-Jun NH(2)-terminal kinase (INK), p38, ATF-2, GSK3, Stall, and Stat3 Additional tests were performed with the p38 inhibitor (p38i) SB203580Results: Studied pathways were activated after impaction with the peak of activity at I hour P188 completely attenuated phosphorylation of Statl and ATF-2 and inhibited p38, Stat3. JNK. ERK, and GSK3 The p38i partially offset phosphorylation of Stat3. GSK3, and ERK suggesting a role of p38 in these three pathways Additionally, the p38i improved cell survival (P = 0 053) and reduced apoptosis (by approximately 20%. P = 0 046, versus almost 40% by P188), thus confirming that P188 acts (at least in part) through the p38 pathwayConclusion: Our results report a novel mechanism I through which P188 exerts its protective effects on cartilage in the model of acute injury In addition to its effect on cellular membrane, P 88 affects stress-related 1)38 signaling, apoptosis-related GSK3, and inflammation-related IL-6 signaling Taken together. these findings suggest that P188 alone or in combination with proanabohc agents may have a therapeutic potential in preventing progressive cartilage degeneration and the development of posttraumatic osteoarthrms