國家衛生研究院 NHRI:Item 3990099045/5605
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    題名: Advanced glycation end products cause collagen II reduction by activating Janus kinase/signal transducer and activator of transcription 3 pathway in porcine chondrocytes
    作者: Huang, CY;Lai, KY;Hung, LF;Wu, WL;Liu, FC;Ho, LJ
    貢獻者: Institute of Cellular and Systems Medicine
    摘要: Objectives. The major risk factor for OA is ageing; however, the mechanisms remain largely unclear. We investigated the effects and mechanisms of advanced glycation end products (AGEs) that accumulate in aged joints in chondrocytes. Methods. Porcine chondrocytes or cartilage fragments were prepared. Gene expression of MMPs and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) was assessed by real-time RT-PCR. Gelatin zymography was used to determine MMP-13 enzyme activity. Histochemistry or immunoblotting analysis was applied to determine the expression of collagen II, proteoglycan and aggrecan. Electrophoretic mobility shift assay and immunoblotting were used to study the activation of signal transducer and activator of transcription 3 (STAT3). Genetic manipulations with short hairpin RNA (shRNA) or dominant negative constructs were applied. Results. AGE enhanced expression and enzyme activity of MMP and ADAMTS genes and resulted in reduction of collagen II. Both janus kinase 2 (JAK2) and JAK3 inhibitors suppressed AGE-induced MMP-13, ADAMTS-4 and ADAMTS-5 expression and enzyme activity. Inhibition of JAK2 or JAK3 prevented AGE-mediated decrease of collagen II in chondrocytes and proteoglycan (aggrecan) degradation in cartilage fragments. In addition, interference of STAT3 expression inhibited AGE-induced MMP-13 and ADAMTS enzyme activities and mRNA levels. Furthermore, expression of the dominant negative receptor of AGE (DN-RAGE) blocked AGE-induced STAT3 phosphorylation. Conclusion. Blocking JAK/STAT3 signalling pathway inhibited AGE-induced activation of MMP-13 and ADAMTS and prevented AGE-mediated decrease of collagen II and proteoglycan (aggrecan). The results indicated that JAK/STAT3 pathway may be a potential target for designing disease-modifying drugs for the treatment of OA.
    日期: 2011-04-10
    關聯: Rheumatology. 2011 Apr 10;50(8):1379-1389.
    Link to: http://dx.doi.org/10.1093/rheumatology/ker134
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1462-0324&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000292832100007
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84862833509
    顯示於類別:[何令君] 期刊論文

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