Shi Jie, Zhang Changjie, Yi Zhongjie, Lan Chunna
Department of Rehabilitation Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
IUBMB Life. 2016 Apr;68(4):293-302. doi: 10.1002/iub.1482. Epub 2016 Feb 13.
Osteoarthritis is a chronic disease characterized by cartilage degeneration and chondrocyte apoptosis. Mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in regulating OA process. Autophagy has an important effect on the OA process, and it is believed to be regulated by MAPKs. To reveal the mechanism and the effect of JNK and p38 MAPKs on matrix metalloproteinase 3 (MMP3) and autophagy in OA, the study established OA model in rabbits, used the measurement of the Osteoarthritis Research Society International scoring system to evaluate OA model, and conducted general observation, histological observation, and Western blotting of JNK, phosphorylate-JNK (P-JNK), p38, phosphorylate-p38 (P-p38), MMP3, and light-chain 3 (LC3)-II/LC3-I to explore the variation of JNK, p38 MAPKs, and autophagy at the early stage of OA. With OA progressing at the early stage, MMP3, P-p38, and P-JNK were gradually upregulated from the baseline to the peak in study groups when compared with the control group; JNK and p38 variated of turbulence without statistical difference; and LC3-II/LC3-I had a decreasing tendency from the 0- to 15-day group. This study identifies that compromised autophagy may be related to the OA progress and that JNK and p38 MAPKs have positive regulation on MMP3 and negative regulation on autophagy. It also implicates a new therapeutic strategy for OA and other degenerate diseases based on selective MAPK inhibitors, reduction of MMP3, and autophagy.
骨关节炎是一种以软骨退变和软骨细胞凋亡为特征的慢性疾病。丝裂原活化蛋白激酶（MAPK）信号通路在调节骨关节炎进程中起关键作用。自噬对骨关节炎进程具有重要影响，并且据信其受MAPKs调控。为揭示JNK和p38 MAPKs对骨关节炎中基质金属蛋白酶3（MMP3）和自噬的作用机制及影响，该研究建立了兔骨关节炎模型，采用国际骨关节炎研究协会评分系统进行评估，并对JNK、磷酸化JNK（P-JNK）、p38、磷酸化p38（P-p38）、MMP3和轻链3（LC3）-II/LC3-I进行大体观察、组织学观察及蛋白质免疫印迹，以探究骨关节炎早期JNK、p38 MAPKs和自噬的变化情况。在骨关节炎早期进展过程中，与对照组相比，研究组中MMP3、P-p38和P-JNK从基线逐渐上调至峰值；JNK和p38变化波动但无统计学差异；且LC3-II/LC3-I在0至15天组呈下降趋势。本研究确定自噬受损可能与骨关节炎进展相关，且JNK和p38 MAPKs对MMP3具有正向调节作用，对自噬具有负向调节作用。它还暗示了一种基于选择性MAPK抑制剂、降低MMP3和自噬的骨关节炎及其他退行性疾病的新治疗策略。
