Dramatic regulation of heparanase activity and angiogenesis gene expression in synovium from patients with rheumatoid arthritis
Dramatic regulation of heparanase activity and angiogenesis gene expression in synovium from patients with rheumatoid arthritis
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DOI：
10.1002/art.23489
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发表时间：
2008-06-01
影响因子：
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通讯作者：
Smith, Paul N.
中科院分区：
文献类型：
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作者：
Li, Rachel W.;Freeman, Craig;Smith, Paul N.
Objective.虽然乙酰肝素酶被认为是一种促血管生成因子，但其在类风湿性关节炎（RA）中的作用尚不清楚。在这项研究中，我们评估了类风湿关节炎（RA）或骨关节炎（OA）患者滑液（SF）和滑膜组织（ST）中的乙酰肝素酶活性，并分析了RA和OA患者ST中血管生成途径相关基因的表达。SF和ST取自RA或OA患者的膝关节和无退行性或炎性关节疾病病史的无症状供体。乙酰肝素酶活性通过使用放射性标记的底物的酶测定来确定，并且通过Western印迹证明ST中乙酰肝素酶的存在。实时定量聚合酶链反应检测ST中血管生成相关基因（包括乙酰肝素酶）的表达。RA患者的SF和ST中乙酰肝素酶活性显著高于OA患者和无症状供体的SF和ST（> 100倍）。类风湿关节炎患者ST中检测到活性乙酰肝素酶，乙酰肝素酶信使RNA表达上调。我们还发现RA滑膜中血管生成基因的表达受到显著调节，并且与乙酰肝素酶活性相关。这些发现是新的，有助于我们了解关节破坏类风湿关节炎，这表明乙酰肝素酶可能是一个可靠的预后因素，类风湿关节炎的进展和治疗RA的一个有吸引力的目标。
Objective. Although heparanase is recognized as a proangiogenic factor, the involvement of heparanase in rheumatoid arthritis (RA) is unclear. In this study, we assessed heparanase activity in synovial fluid (SF) and synovial tissue (ST) from patients with RA or osteoarthritis (OA), and analyzed the expression of angiogenic pathway-focused genes in ST from RA and OA patients.Methods. SF and ST were obtained from the knees of patients with either RA or OA and from asymptomatic donors with no documented history of degenerative or inflammatory joint diseases. Heparanase activity was determined by an enzymatic assay using a radiolabeled substrate, and the presence of heparanase in ST was demonstrated by Western blotting. The expression of angiogenesis genes, including heparanase, in ST was analyzed by real-time quantitative polymerase chain reaction.Results. Heparanase activity was dramatically higher (> 100-fold) in SF and ST from RA patients than in SF and ST from OA patients and asymptomatic donors. Active heparanase enzyme was detected and heparanase messenger RNA was up-regulated in ST from RA patients. We also found that angiogenesis gene expression was significantly regulated in RA synovium, and was correlated with heparanase activity.Conclusion. These findings are novel and contribute to our understanding of joint destruction in RA, suggesting that heparanase may be a reliable prognostic factor for RA progression and an attractive target for the treatment of RA.