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Dynamic activation of bone morphogenetic protein signaling in collagen induced arthritis supports their role in joint homeostasis and disease

机译:胶原诱导的关节炎中骨形态发生蛋白信号的动态激活支持其在关节稳态和疾病中的作用

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摘要

ABSTRACT: INTRODUCTION: Rheumatoid arthritis is a chronic systemic auto-immune disease affecting peripheral joints and leading to loss of joint function. The severity and outcome of disease are dependent on the balance between inflammatory/destructive and homeostatic or repair pathways. Increasing evidence suggests a role for bone morphogenetic protein (BMP) signaling in joint homeostasis and disease. METHODS: Activation of BMP signaling in collagen induced arthritis as a model of rheumatoid arthritis was studied by immunohistochemistry and western blot for phosphorylated-SMAD1/5 at different time points. Expression of different BMP ligands and noggin, a BMP antagonist, was determined on synovium and cartilage extracts of arthritic knees, at different time points, with quantitative PCR. At the protein level, BMP2 and BMP7 were studied with immunohistochemistry. Finally, the effect of anti-tumor necrosis factor alpha (TNFalpha) treatment on the expression of BMP2, BMP7 and growth and differentiation factor 5 (GDF5) in synovium and cartilage of arthritic knees was investigated. RESULTS: A time-dependent activation of BMP signaling pathway in collagen induced arthritis was demonstrated with a dynamic and characteristic expression pattern of different BMP subfamily members in synovium and cartilage of arthritic knees. As severity increases, the activation of BMP signaling becomes more prominent in the invasive pannus tissue. BMP2 is present in cartilage and the hyperplastic lining layer. BMP7 is found in the sublining zone and inflammatory infiltrate. Treatment with etanercept slowed down progression of disease, but no change in expression of GDF5, BMP2 and BMP7 in synovium was found; in the cartilage, however, blocking of TNFalpha increased expression of BMP7. CONCLUSIONS: BMP signaling is dynamically activated in collagen induced arthritis and is partly TNFalpha-independent. TNFalpha blocking increased the expression of BMP7 in the articular cartilage, possibly enhancing anabolic mechanisms. Different types of source and target cells are recognized. These data further support a role for BMP signaling in arthritis.
机译:摘要:简介:类风湿关节炎是一种慢性全身性自身免疫性疾病,会影响周围的关节并导致关节功能丧失。疾病的严重程度和结果取决于炎症/破坏性和体内平衡或修复途径之间的平衡。越来越多的证据表明骨形态发生蛋白(BMP)信号在关节稳态和疾病中的作用。方法:通过免疫组织化学和蛋白质印迹法研究磷酸化SMAD1 / 5在不同时间点在类风湿性关节炎模型中胶原诱导的关节炎中BMP信号的激活。在不同时间点,通过定量PCR测定关节炎膝关节滑膜和软骨提取物中不同BMP配体和头蛋白(BMP拮抗剂)的表达。在蛋白质水平上,使用免疫组织化学研究了BMP2和BMP7。最后,研究了抗肿瘤坏死因子α(TNFalpha)处理对关节炎膝关节滑膜和软骨中BMP2,BMP7和生长分化因子5(GDF5)表达的影响。结果:在关节炎的膝关节滑膜和软骨中,不同BMP亚家族成员的动态和特征性表达模式证明了胶原诱导的关节炎中BMP信号通路的时间依赖性激活。随着严重程度的增加,BMP信号的激活在侵入性血管pan组织中变得更加突出。 BMP2存在于软骨和增生性衬里层中。 BMP7被发现在下界区和炎性浸润。依那西普治疗减慢了疾病的进展,但未发现滑膜中GDF5,BMP2和BMP7的表达发生变化。然而,在软骨中,TNFα的阻断增加了BMP7的表达。结论:BMP信号在胶原诱导的关节炎中是动态激活的,并且部分不依赖TNFα。 TNFalpha阻断增加了BMP7在关节软骨中的表达,可能增强了合成代谢机制。识别出不同类型的源细胞和目标细胞。这些数据进一步支持了BMP信号转导在关节炎中的作用。

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