abolic disturbance induced by IL 1B, the NF ��B signaling is believed to be mainly responsible for the inflammatory activity of IL 1B. Meanwhile, recent data suggested that it was SAP JNK and p38 signaling pathway that mediated the IL 1B induced suppression of ylosyltransferase I gene e pression and the subsequent GAG synthesis in human articular selleck chem inhibitor chondrocytes. In the present study, we also observed that inhibition of both p38 MAPK and SAP JNK led to an obvious attenuation of the IL 1B induced suppression on the gene e pression of UGDH and its trans regulators, which indicated that IL 1B could suppress UGDH gene e pression and consequently inhibit PGs synthesis in articular chondrocytes, which might suppress matri restore and contribute to the OA progress.
Sp1 binds to the GC or GT rich motifs of UGDH promoter sequence and promote transcriptional activity of UGDH gene, while Sp3 and c Kro were suggested to be playing the negative regulatory roles. Inhibition of Sp1 e pression with siRNA resulted in attenuation of UGDH enzyme activity, reduction of UGDH gene promoter activity and consequent depression of UGDH mRNA levels. Meanwhile, TGF B stimulated UGDH gene e pression through increasing DNA binding of Sp1 to the sequences located in UGDH promoter. It was also reported that IL 1B inhibited COL2A1 gene transcription by increasing the Sp3 Sp1 ratio and inhibiting the binding of Sp1 and Sp3 to the promoter. Binding to the same sequence that binds Sp1 and Sp3, c Kro was suggested to act in concert with Sp1 and Sp3 to modulate UGDH gene e pression.
Overe pression of c Kro gene in rabbit articular chondrocytes led to marked decrease in mRNA and protein level of UGDH gene, which was mediated by the increased binding of c Kro to the cis sequence located in UGDH promoter. In the present study, IL 1B altered the gene e pression of Sp1, Sp3 and c Kro , decreased the nuclear translocation of Sp1 protein, and increased the Sp3 Sp1 ratio, as well as c Kro Sp1 ratio. Altogether, it suggests that Sp1, Sp3 and c Kro mediated the modulation of IL 1B on UGDH gene e pression. Sp3 Sp1 ratio and c Kro Sp1 ratio in chondrocytes might be helpful in estimating the effects of drugs, cytokines or growth factors on cartilage homeostasis. Moreover, decreasing Sp3 Sp1 and c Kro Sp1 ratio could help to restore the cartilage phenotype in osteoarthritic joints.
Batimastat Conclusions In conclusion, UGDH plays a critical role in the PGs synthesis definitely of articular chondrocytes, of which, the e pression was suppressed in advanced OA. Meanwhile, IL 1B suppresses UGDH gene e pression through activating SAP JNK and p38 MAPK pathways and subsequently modulating the gene e pression of UGDHs trans regulators including Sp1, Sp3 and c Kro . Accordingly, we speculate that IL 1B might be involved in the suppression of UGDH gene e pression in OA, which would probably contribute to the OA pathogenesis. Introduction The prevalence of obesity has steadily increased over the past three decades all over the world,