Chen et al. showed that human cartilage expressed only AdipoR1. However, our study showed that both AdipoR1 and AdipoR2 are expressed in human cartilage tissue, consistent with the results of Lago et al. A heterogeneous distribution of AdipoR1 and AdipoR2 on chondrocytes might be a factor that explains the difference between our results and those of the others. In our study, the expression of AdipoR2 was higher in terms of the immunostaining intensity as well as the percentage of stained cells, but the increase rate of AdipoR1 was as twice as high as that of AdipoR2, when nonlesional and lesional cartilage areas were compared. This finding suggests that the change of AdipoR1 expression might better reflect the cartilage catabolic state than that of AdipoR2, and that the AdipoR1 AMPK pathway could be associated with cartilage catabolism.
It has been well established that adiponectin activates AMPK. Lago et al. reported that the AMPK Akt signaling pathway is involved in iNOS and selleck chemical MMP 3 induction by adiponectin in the murine chondrocyte ATDC5 cell line. In addition, adiponectin activated the AMPKp38NF B axis in human synovial fibroblasts to induce IL 6 production. Conversely, in our study, AMPKJNK pathways are the major signaling pathway involved in adiponectin mediated induction of iNOS and MMPs in human OA chondrocytes, whereas the AMPKAkt or AMPKp38 pathway is partially involved in MMP 13 or MMP 3 induction, respectively. The JNK pathway is one of the signaling intermediates activated by adiponectin, and adiponectin induced JNK activation has been shown to follow AMPK activation.
Furthermore, JNK is involved in MMPs and iNOS expression in human articular chondrocytes. Therefore, we expect that adiponectin induces iNOS and MMP expression via JNK downstream to AMPK in human chondrocytes and that the AMPKJNK axis is a major signaling inhibitor supplier system responsible for the adi ponectin induced degradation of cartilage matrix. Because NO can upregulate the expression or activity of MMPs, we determined whether NO mediates adiponectin induced synthesis of MMPs. Unexpectedly, the expression of MMPs was further increased by adipo nectin after pretreatment with a nonspecific NOS and a specific iNOS inhibitor. This finding is consistent with the previous observation by Hattori et al. in which adiponectin induced NF B activation was further enhanced by a nonspecific NO inhibitor, L NMMA, in human umbilical vein endothelial cells.
Interestingly, LY294002, a PI3 KAkt kinase inhibitor, significantly suppressed NO production, whereas it caused a higher MMP 3 production in adiponectin treated ATDC5 cells in the study of Lago et al. In this context, we are tempted to speculate that NO serves as a negative feedback regulator of adiponectin action in cartilage, and that this negative feedback may lead to the delayed effects of adiponectin on the OA cartilage catabolism when compared with those of IL 1b in our study.