SP600125 Restored TNF-α-Induced Impaired Chondrogenesis in Bone Mesenchymal Stem Cells and Its Antiosteoarthritis Effect in Mice.

Inflammation, the main factor in the progression of osteoarthritis (OA), impairs the chondrogenesis of bone mesenchymal stem cells (BMSCs), which is an appealing process to target to regenerate impaired articular cartilage. This article aimed to investigate whether SP600125, a competitive ATP-specific inhibitor of the JNK pathway, could promote the chondrogenesis of BMSCs by enhancing their anti-inflammatory capacity. Chondrogenic differentiation was assessed by Alcian blue staining, immunofluorescence staining, and Western blot. The inflammation level was associated with the expression of matrix metalloproteinases (Mmp), evaluated by Western blot. Intra-articular injection of BMSCs pretreated with or without SP600125 was carried out on C57BL/6 mice after inducing OA by surgical destabilization of the medial meniscus. Safranin O-fast green (SO) and hematoxylin-eosin staining were employed to evaluate the cartilage destruction and immunohistochemical analysis was adopted to detect the expression of Col2 and Mmp-13 proteins in the mouse knee joint. We showed that SP600125 could inhibit inflammation induced by tumor necrosis factor-α (TNF-α) and promote the chondrogenesis of BMSCs. In the presence of TNF-α, the expression of aggrecan (Agc) and collagen type II alpha 1 (Col2) was significantly decreased compared with that in the control group and increased with the addition of SP600125. Moreover, the expression of Mmp-1, Mmp-3, and Mmp-13 was increased in BMSCs treated only with TNF-α and downregulated in SP600125-treated BMSCs. In vivo study showed that SP600125 could enhance protective effects of BMSCs on OA mice. Our results indicated that SP600125 rescued the chondrogenesis of BMSCs by inhibiting inflammation induced by TNF-α, which provides a theoretical basis for solving the problem of cartilage repair under inflammatory conditions.

Downregulation of CDK-8 inhibits colon cancer hepatic metastasis by regulating Wnt/ß-catenin pathway.

Liver metastasis is a major cause of mortality from colon cancer. To investigate the role of cyclin-dependent kinase 8 (CDK8) in the progression of colon cancer hepatic metastasis. In this present study, human colon cancer HCT116 or HCT116-LUC-GFP cells were transfected with Lentiviral vector-mediated knockdown of CDK-8. After transfection, metastasis and invasion potential of colon cancer cell was investigated by wound healing and transwell invasion assays, respectively. A mice model of colon cancer liver metastases was established and observed with bioluminescence imaging. The protein expression of CDK-8, ß-catenin, E2F1, MMP-7 and E-cadherin in liver tissues were detected by Western Blot. Our results revealed that lentiviral vector-mediated knockdown of CDK-8 inhibited metastasis and invasion of colon cancer cells in vitro and in vivo, respectively. Protein expression of CDK-8, ß-catenin, MMP-7 and E-cadherin were inhibited, but protein expression of E2F1 was enhanced. In sum, our data provided compelling evidence that CDK-8 played a significant role in colon cancer hepatic metastasis by regulating the Wnt/ß-catenin signal pathway and might sever as a potential therapeutic target for colon cancer patients.