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 (Pp38), 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. V C 2016 IUBMB Life, 68(4): [293][294][295][296][297][298][299][300][301][302] 2016

Osteoarthritis (OA) is a complex disease that affects articular joints and may cause disability. The incidence of OA is extremely high. Most elderly people have the symptoms of osteoarthritis. The physiotherapy of OA is time consuming, and the chances of full recovery from OA are very minimal. The most effective way of fighting OA is early diagnosis and early intervention. Liquid biopsy has become a popular noninvasive test. To find the blood gene expression signature for OA, we reanalyzed the publicly available blood gene expression profiles of 106 patients with OA and 33 control samples using an automatic computational pipeline based on advanced feature selection methods. Finally, a compact 23-gene set was identified. On the basis of these 23 genes, we constructed a Support Vector Machine (SVM) classifier and evaluated it with leave-one-out cross-validation. Its sensitivity (Sn), specificity (Sp), accuracy (ACC), and Mathew's correlation coefficient (MCC) were 0.991, 0.909, 0.971, and 0.920, respectively. Obviously, the performance needed to be validated in an independent large dataset, but the in-depth biological analysis of the 23 biomarkers showed great promise and suggested that mRNA surveillance pathway and multicellular organism growth played important roles in OA. Our results shed light on OA diagnosis through liquid biopsy.

Osteoarthritis (OA) is a chronic, age-related osteoarthropathy that causes a considerable decline in quality of life, as well as economic losses due to its high incidence and poor prognosis. Mitogen-activated protein kinases (MAPKs) regulate multiple cellular processes, including proliferation, differentiation and apoptosis, in certain diseases, such as cancer, diabetes and Alzheimer's disease. The present study aimed to investigate the regulatory role of the MAPK signaling pathway in early-stage OA. A rabbit model of early-stage OA was induced by treatment with the enzyme papain. U0126 [an extracellular signal-regulated kinase (ERK) inhibitor], SP600125 [a Jun NH2-terminal kinase (JNK) inhibitor] and SB203580 (a p38 inhibitor) were administered to the rabbits via intra-articular injection. The severity of OA was assessed by histological examination using H&E, toluidine blue and safranin-O/fast green staining, as well by analyzing the glycosaminoglycan (GAG) content and determining the OA Research Society International (OARSI) score. Western blotting was used to detect the protein expression levels of matrix metalloproteinase-3 (MMP3), ERK, phosphorylated (p)-ERK, p38, p-p38, JNK, p-JNK, Beclin1, UNC-51-like kinase 1 (ULK1) and microtubule-associated protein 1 light chain 3 (LC3)II/I. U0126, SP600125 or SB203580 treatment significantly decreased the OARSI scores and significantly increased the GAG levels in the cartilaginous tissues of OA model rabbits. These results indicated that the MAPK inhibitors reduced the severity of OA-induced injury at the early stage. Western blotting results demonstrated that MAPK inhibition significantly decreased the protein expression levels of MMP3 in OA cartilage. The protective effect of MAPK inhibitors in OA was mediated via the activation of autophagy, as demonstrated by the increased protein expression levels of LC3II/I, ULK1 and Beclin1. Overall, the data indicated that MAPK inhibitors may exert a protective effect against OA by restoring compromised autophagy. Furthermore, the present study suggested that MAPK inhibitors may represent a potential pharmacological strategy for treating OA in the future.

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