On the other hand, these findings can somehow explain the ROS contribution to the pathogenesis of OA, no changes in glucose incorporation by normal chondro cytes can suggest a protective mechanism against the selleck CHIR99021 deleterious effects of excessive intracellular glucose, as seen in other cells, and the incapacity of OA chon drocytes to regulate this can trigger ROS accumulation in OA cartilage. Others authors have reported that basal glucose uptake is identical in normal and OA chondro cytes, the reasons for these discrepancies are unclear Inhibitors,Modulators,Libraries but the observed differences may be related to the culture conditions used in these studies. Conclusions The new generation donor NOC 12 mimics the meta bolic OA situation much better than the classical NO donor SNP.

Taking account of all the results obtained in this study, previous findings using SNP have to be considered Inhibitors,Modulators,Libraries very cautiously, and most of the effects observed in human chondrocytes probably cannot be attributed exclusively to NO. Introduction Articular cartilage is an avascular, non insulin sensitive Inhibitors,Modulators,Libraries tissue that utilizes glucose as the main energy source and as a precursor for glycosaminoglycan synthesis and a regu lator of gene expression. Degradation of articular cartilage is a hallmark of osteoarthritis and is associated with aberrant glucose metabolism. On the other hand, the pathogenesis of OA is characterized by the pro duction of high amounts of nitric oxide, conse quence of up regulation of chondrocyte inducible nitric oxide synthase induced by inflammatory cytokines, such as IL 1b and TNFa, and other factors.

Although it has been reported that NO causes chon drocyte apoptosis, production of high Inhibitors,Modulators,Libraries levels of endogenous NO by over expression of the iNOS gene in transfected chondrocytes has not been found to cause cell death. Other reports have proposed NO to be a physiologic regulator of mitochondrial respiration in chondrocytes. A variety of NO donors have been Inhibitors,Modulators,Libraries demonstrated to suppress energy production by mitochondrial respiration in different cell types, an effect enhanced at low oxygen tensions, and firstly reported in chondrocytes by Johnston and colla borators. Chondrocytes are highly glycolytic resident cells of articular cartilage that metabolize glucose as a primary substrate for ATP production. However, oxygen does diffuse into articular cartilage and articular chon drocytes possess mitochondria and respire in vivo.

The superficial and middle zones of articular cartilage are not anoxic, and in this context, mitochondrial oxidative phosphorylation is 18 times as effi cient in ATP generation as is glycolysis. Further more, OXPHOS may account for up to one fourth of total steady state ATP production within articular carti lage, and possibly more under conditions of increased energy demands associated with cartilage stress.