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A central feature of osteoarthritis (OA) is the loss of articular cartilage, which is primarily attributed to cartilage breakdown. A group of metalloproteinases termed the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family are reported to be important in cartilage breakdown. Recent studies have suggested that ADAMTS-4 is a major contributor to the pathogenesis of OA and that syndecan-1 is closely associated with activation of ADAMTS-4 in human chondrocytes. Accumulating evidence also suggests that cannabinoids have chondroprotective effects. The current study explored the effects of synthetic cannabinoid WIN-55,212-2 mesylate (WIN-55) on the expression of syndecan-1 and ADAMTS-4, as well as ADAMTS-4 activity, in unstimulated and interleukin (IL)-1β-stimulated OA chondrocytes. Primary human OA articular chondrocytes were treated with WIN-55 in the presence or absence of IL-1β and cannabinoid receptor antagonists. The results of the present study demonstrated that WIN-55 inhibited ADAMTS-4 activity in unstimulated and IL-1β-stimulated primary human OA articular chondrocytes in a concentration-dependent manner. Cannabinoid receptor type 1 (CB1) and 2 (CB2) were constitutively expressed in human OA articular chondrocytes. Furthermore, selective CB2 antagonist, JTE907, but not selective CB1 antagonist, MJ15, abolished the inhibitory effect of WIN-55 on ADAMTS-4 activity. WIN55 inhibited the expression of syndecan-1 but not ADAMTS-4, and overexpression of syndecan-1 reversed the inhibitory effect of WIN-55 on the ADAMTS-4 activity in unstimulated and IL-1β-stimulated human OA articular chondrocytes. Despite having no significant effect on syndecan-1 gene promoter activity, WIN-55 markedly decreased the stability of syndecan-1 mRNA via CB2. In conclusion, to the best of our knowledge, the present study provides the first in vitro evidence supporting that the synthetic cannabinoid WIN-55 inhibits ADAMTS-4 activity in unstimulated and IL-1β-stimulated human OA articular chondrocytes by decreasing the mRNA stability/expression of syndecan-1 via CB2. This suggests a novel mechanism by which cannabinoids may prevent cartilage breakdown in OA. In addition, it also provides novel insights into the pharmacological effects of synthetic cannabinoids on OA. [ABSTRACT FROM AUTHOR]

Triptolide (TL) is known to suppress the proliferation of a number of pancreatic cancer cell lines in vitro. Marked antitumor effects were also observed in a xenograft model of pancreatic cancer. Hypoxia-inducible factor-1α (HIF-1α) is highly expressed in pancreatic cancer cells lines. The present study therefore tested the hypothesis that suppression of HIF-1α is associated with the antitumor activity of TL. Quantitative polymerase chain reaction and western blot analysis were used to determine the level of gene expression. A xenograft tumor model of pancreatic cancer was established in athymic nude mice and the tumor size was measured to evaluate the outcome of TL treatment. Immunohistochemistry was used to detect the expression of HIF-1α and vascular endothelial growth factor (VEGF), and to assess microvessel density. Microarray was used to investigate gene expression in pancreatic cancer cells following TL treatment. The expression of HIF-1α was shown to be reduced in pancreatic cell lines following treatment with TL, and this effect occurred in a dose-dependent manner. In a xenograft model of pancreatic cancer, reduced levels of HIF-1α were also observed in mice that were treated with TL. Furthermore, the expression of VEGF, which is a direct target of HIF-1α, was also suppressed, and the microvessel density of tumor tissues was consequently reduced. A microarray analysis of gene expression was performed in order to investigate the potential mechanisms underlying the antitumor activity of TL. The results showed that 11 genes, including c-Myc, SOX9 and Ets2, were downregulated at an early stage following treatment with TL. A recent study indicated that overexpression of c-Myc in colon cancer cells promotes increased expression of HIF-1α and VEGF. Therefore, TL may suppress HIF-1α through a c-Myc-dependent mechanism, which is involved in antitumor effects in mouse models of pancreatic cancer. [ABSTRACT FROM AUTHOR]