Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes.
Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes.
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WNT5A诱导人关节软骨细胞中的分解代谢信号传导和基质金属蛋白酶的产生。
DOI：
10.1016/j.joca.2017.05.018
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发表时间：
2017-09
影响因子：
7
通讯作者：
Loeser RF
中科院分区：
文献类型：
--
作者：
Huang G;Chubinskaya S;Liao W;Loeser RF
异常的Wnt信号传导可能导致骨关节炎（OA），但涉及的Wnt家族成员尚未完全确定。本研究的目的是研究Wnt 5a作为OA软骨破坏的潜在介质的作用。使用正常和OA人关节软骨进行免疫组织化学以检测Wnt 5a。培养的正常人软骨细胞用纤连蛋白片段（FN-f）作为分解代谢刺激物或重组Wnt 5a蛋白处理，使用或不使用一组信号传导抑制剂进行预处理。通过实时定量PCR测定Wnt 5a、合成代谢基因和分解代谢基因的表达。通过免疫印迹分析Wnt 5a蛋白和基质金属蛋白酶（MMPs）的产生以及信号蛋白的活化。Wnt 5a存在于OA改变的人关节软骨中，并且其表达和分泌在FN-f刺激的软骨细胞中增加。FN-f通过JNK和ERK途径刺激Wnt 5a的产生。Wnt 5a在处理48小时后降低聚集蛋白聚糖基因表达。Wnt 5a似乎促进正常人软骨细胞中MMP 1、MMP-3和MMP-13的表达以及MMP 1和MMP 13蛋白的产生。Wnt 5a抑制肽不影响FN-f诱导的MMP产生。Wnt 5a激活β-catenin非依赖性信号传导，包括钙调蛋白依赖性蛋白激酶II（CaMK II）、JNK、p38、ERK 1/2、p65和Akt。通过特异性信号传导抑制剂抑制JNK、p38、ERK、PI-3激酶和CaMKII抑制Wnt 5a介导的MMP 1和MMP 13的产生。Wnt 5a存在于人OA软骨中，并且可以通过非经典Wnt信号传导促进软骨细胞分解代谢活性，这表明在OA中的潜在作用。
Aberrant Wnt signaling may contribute to osteoarthritis (OA) but the Wnt family members involved have not been fully identified. The purpose of this study was to investigate the role of Wnt5a as a potential mediator of cartilage destruction in OA. Immunohistochemistry to detect Wnt5a was performed using normal and OA human articular cartilage. Cultured normal human chondrocytes were treated with fibronectin fragments (FN-f) as a catabolic stimulus or recombinant Wnt5a protein with or without pretreatment using a panel of signaling inhibitors. Expression of Wnt5a, anabolic genes and catabolic genes were determined by quantitative real-time PCR. Production of Wnt5a protein and matrix metalloproteinases (MMPs) as well as activation of signaling proteins were analyzed by immunoblotting. Wnt5a was present in human articular cartilage with OA changes and its expression and secretion were increased in FN-f stimulated chondrocytes. FN-f stimulated Wnt5a production through the JNK and ERK pathways. Wnt5a reduced aggrecan gene expression after 48 hours of treatment. Wnt5a seemed to promote MMP1, -3, and -13 expression as well as MMP1 and MMP13 protein production in normal human chondrocytes. Wnt5a inhibitor peptides did not affect FN-f induced MMP production. Wnt5a activated β-catenin independent signaling including calmodulin-dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt. Inhibition of JNK, p38, ERK, PI-3 kinase and CaMKII by specific signaling inhibitors suppressed Wnt5a mediated MMP1 and MMP13 production. Wnt5a is present in human OA cartilage and can promote chondrocyte catabolic activity through non-canonical Wnt signaling, which suggests a potential role in OA.
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影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
DOI：
10.1007/s00018-015-2076-y
发表时间：
2016-02
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Kumawat K;Gosens R
通讯作者：
Gosens R
DOI：
10.1073/pnas.0909409106
发表时间：
2009-11-17
影响因子：
11.1
作者：
Jenei, Veronika;Sherwood, Victoria;Andersson, Tommy
通讯作者：
Andersson, Tommy
影响因子：
--
作者：
Loeser, RF;Pacione, CA;Chubinskaya, S
通讯作者：
Chubinskaya, S
影响因子：
--
作者：
Forsyth, CB;Pulai, J;Loeser, RF
通讯作者：
Loeser, RF