Objective. Long noncoding RNAs (lncRNAs) play crucial regulatory roles in diverse biologic processes, but knowledge of lncRNAs in osteoarthritis (OA) is limited. The aim of this study was to identify lncRNA expression in articular cartilage and to explore the function of cartilage injury-related lncRNAs (lncRNA-CIR) in OA.Methods. To identify lncRNAs specifically expressed in OA cartilage, we compared the expression of lncRNAs in OA cartilage with that in normal cartilage using microarray and quantitative polymerase chain reaction (qPCR) analyses. In OA cartilage, lncRNA-CIR was specifically, differentially, and highly expressed. The function of lncRNA-CIR was determined by silencing and overexpression in vitro. Extracellular matrix (ECM)-related molecules were detected by qPCR, Western blot, and immunofluorescence analyses.Results. Up to 152 lncRNAs were found to be differentially expressed (>8-fold) in OA and normal cartilage (82 lncRNAs more highly expressed and 70 less highly expressed in OA cartilage than in normal cartilage). A specific differentially expressed lncRNA-CIR was selected according to the results of the higher expression in OA cartilage and OA chondrocytes. The expression of lncRNA-CIR increased in chondrocytes with in vitro treatment with interleukin-1␤ and tumor necrosis factor ␣. Silencing of lncRNA-CIR by small interfering RNA promoted the formation of collagen and aggrecan and reduced the expression of matrixdegrading enzymes, such as MMP13 and ADAMTS5. The expression of collagen and aggrecan was reduced, whereas the expression of matrix-degrading enzymes was increased, after overexpression of lncRNA-CIR.Conclusion. The results indicate that lncRNA-CIR contributes to ECM degradation and plays a key role in the pathogenesis of OA. We propose that lncRNA-CIR could be used as a potential target in OA therapy.Osteoarthritis (OA) is a degenerative joint disease characterized by degradation of articular cartilage, thickening of subchondral bone, and formation of osteophytes (1). OA is associated with age-related loss of homeostatic balance. Cartilage cellularity in OA is reduced by chondrocyte death, and chondrocytes are stimulated by cytokines and growth factors to a catabolic and abnormal differentiation that leads to degradation of the extracellular matrix (ECM) (2-5). Degradation of the ECM is complicated, for it involves genetic, developmental, biochemical, and biomechanical factors. The molecular mechanisms involved in the maintenance of articular cartilage have been characterized in order to develop new therapeutic interventions (6,7).The human transcriptome comprises not only protein-coding messenger RNAs (mRNAs), but also a large amount of non-protein-coding transcripts that have structural, regulatory, or unknown functions (8). Although studies of small noncoding RNAs (microRNAs, consisting of 18-200 nucleotides) have dominated the field of RNA biology in recent years (9-11), multiple studies have indicated that promising new molecules, namely, long noncoding RNAs (lncRNAs),

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BackgroundIslet 1 (ISL1), a LIM-homeodomain transcription factor is essential for promoting pancreatic islets proliferation and maintaining endocrine cells survival in embryonic and postnatal pancreatic islets. However, how ISL1 exerts the role in adult islets is, to date, not clear.Methodology/Principal FindingsOur results show that ISL1 expression was up-regulated at the mRNA level both in cultured pancreatic cells undergoing glucose oxidase stimulation as well in type 1 and type 2 diabetes mouse models. The knockdown of ISL1 expression increased the apoptosis level of HIT-T15 pancreatic islet cells. Using HIT-T15 and primary adult islet cells as cell models, we show that ISL1 promoted adult pancreatic islet cell proliferation with increased c-Myc and CyclinD1 transcription, while knockdown of ISL1 increased the proportion of cells in G1 phase and decreased the proportion of cells in G2/M and S phases. Further investigation shows that ISL1 activated both c-Myc and CyclinD1 transcription through direct binding on their promoters.Conclusions/SignificanceISL1 promoted adult pancreatic islet cell proliferation and probably by activating c-Myc and CyclinD1 transcription through direct binding on their promoters. Our findings extend the knowledge about the crucial role of ISL1 in maintaining mature islet cells homeostasis. Our results also provide insights into the new regulation relationships between ISL1 and other growth factors.

The cardiac transcription factor NKX2.5 plays a crucial role in cardiomyogenesis, but its mechanism of regulation is still unclear. Recently, epigenetic regulation has become increasingly recognized as important in differentiation and development. In this study, we used P19CL6 cells to investigate the regulation of Nkx2.5 expression by methylation and acetylation during cardiomyocyte differentiation. During the early stage of differentiation, Nkx2.5 expression was upregulated, but the methylation status of the Nkx2.5 promoter did not undergo significant change; while the acetylation levels of histones H3 and H4 were increased, accompanied by a significant reduction in Hdac1 expression. Suppression of Hdac1 activity stimulated cardiac differentiation accompanied by increased expression of cardiac-specific genes and cell cycle arrest. Overexpression of Hdac1 inhibited cardiomyocyte formation and downregulated the expressions of Gata4 and Nkx2.5. Mimicking induction of the WNT pathway inhibited Hdac1 expression with upregulated Nkx2.5 expression. WNT3a and WNT3 downregulated the expression of Hdac1, contrary to the effect of SFRP2 and GSK3beta. Cotransfection of beta-catenin and Lef1 significantly downregulated the expression of Hdac1. Our data suggest that WNT signaling pathway plays important roles in the regulation of Hdac1 during the early stage of cardiomyocyte differentiation and that the downregulation of Hdac1 promotes cardiac differentiation.

Background microRNAs (miRNAs) are a class of small, non-coding endogenous RNAs that post-transcriptionally regulate some protein-coding genes. miRNAs play an important role in many cardiac pathophysiological processes, including myocardial infarction, cardiac hypertrophy, and heart failure. miR-499, specifically expressed in skeletal muscle and cardiac cells, is differentially regulated and functions in heart development. However, the function of miR-499 in mature heart is poorly understood.Results We report that cardiac-abundant miR-499 could protect neonatal rat cardiomyocytes against H2O2-induced apoptosis. Increased miR-499 level favored survival, while decreased miR-499 level favored apoptosis. We identified three proapoptotic protein-coding genes—Pdcd4, Pacs2, and Dyrk2—as targets of miR-499. miR-499 inhibited cardiomyocyte apoptosis through its suppressive effect on Pdcd4 and Pacs2 expression, thereby blocking Bid expression and BID mitochondrial translocation. We also found that H2O2-induced phosphorylation of c-Jun transcriptionally upregulated miR-499 expression via binding of phosphorylated c-Jun to the Myh7b promoter.Conclusions Our results revealed that miR-499 played an inhibiting role in the mitochondrial apoptosis pathway, and had protective effects against H2O2-induced injury in cardiomyocytes.