Enhanced SOCS3 in osteoarthiritis may limit both proliferation and inflammation.

Osteoarthritis (OA) is a degenerative joint disease that is characterized by localized inflammatory and secondary proliferative changes. Suppressor of cytokine signaling 3 (SOCS3) is elevated during OA development. We investigated the effects of this protein on human chondrocyte survival in OA and the inflammatory response together with the mechanisms of these effects. Small interfering RNA (siRNA) was used to knock down the expression of SOCS3 in interleukin(IL)-1ß-induced primary human osteoarthritic chondrocytes. We found that siRNA-mediated SOCS3 knock-down in human osteoarthritic chondrocytes increased production of IL-1ß-induced prostaglandin E2, cell growth, transcript level and nuclear translocation of cyclin D1. Silencing of SOCS3 resulted in altered expression of nuclear factor-kappa-B (NF-κB) and cyclooxygenase (COX2). Our findings indicate that enhanced SOCS3 could have contradictory influences on OA development. SOCS3 might protect damaged joints by its anti-inflammatory effect and by inhibition of over-augmented cartilage tissue repair, which could exhibit inhibitory properties for joint inflammation, abnormal chondrocyte clustering and osteophyte formation in OA. On the other hand, SOCS3 might reduce chondrocyte growth response, which would delay repair of subchondral cancellous bone damage in OA owing to its anti-proliferation effect. The anti-inflammation and growth inhibition effects exhibited by enhanced SOCS3 in OA appear to be related to its capacity to down-regulate expression levels of NF-κB and COX2.

Genome-wide analysis of DNA methylation variations caused by chronic glucolipotoxicity in beta-cells.

There is a growing body of literature suggesting the role of interactions between genes and the environment in development of type 2 diabetes mellitus (T2DM). However, the interplay between environment and genetic in developing and progressing T2MD is not fully understood. To determine the effects of high-glucose-lipid on the status of DNA methylation in beta cells, and clarify the mechanism of glucolipotoxicity on beta-cell deterioration, the DNA methylation profile was detected in beta-cells cultured with high-glucose-lipid medium.We utilized a high throughput NimbleGen RN34 CpG Island & Promoter Microarray to investigate the DNA methylation profile in beta-cells cultured with high-glucose-lipid medium. To validate the results of microarray, the immunoprecipitation (MeDIP) PCR was used to test the methylation status of some selected genes. The mRNA and protein expression of insulin and Tcf7l2 in these cells were quantified by RT-PCR and western blot, respectively.We have identified a lot of loci which experienced aberrant DNA methylation in beta-cells cultured with high-glucose-lipid medium. The results of MeDIP PCR were consistency to the microarray. An opposite regulation in transcription and translation of Tcf7l2 gene was found. Furthermore, the insulin mRNA and protein expression in beta-cells also decreased after cultured with high-glucose-lipid medium compared with the control cells.We conclude that chronic glucolipotoxicity could induce aberrant DNA methylation of some genes and may affect these genes expression in beta-cells, which might contribute to beta-cell function failure in T2DM and be helpful to explain, at least partially, the mechanism of glucolipotoxicity on beta-cells deterioration.