Wnt/β-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes:: its possible role in joint degeneration
Wnt/β-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes:: its possible role in joint degeneration
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DOI：
10.1038/labinvest.3700747
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发表时间：
2008-03-01
影响因子：
5
通讯作者：
Enomoto-Iwamoto, Motomi
中科院分区：
文献类型：
--
作者：
Yuasa, Takahito;Otani, Tomohiro;Enomoto-Iwamoto, Motomi
合成代谢和分解代谢机制之间的良好平衡维持了关节软骨中的细胞外基质稳态，并且向降解的转变与关节疾病如骨关节炎相关。为了测试Wnt/β-连环蛋白信号传导途径在这些分解代谢转变中的可能参与、相关性和意义，通过Wnt 3A处理或强制表达组成型活性β-连环蛋白（CA-β-连环蛋白）对兔关节软骨细胞培养物进行β-连环蛋白信号传导的实验性活化。这两种干预措施都会激发较强的明胶酶活性，并刺激基质金属蛋白酶-3和-13以及具有血小板反应蛋白基序的解整合素样金属蛋白酶（ADAMTS）-4和-5蛋白酶的基因表达。此外，Wnt3A处理加性增强了白细胞介素-1 β的作用，白细胞介素-1 β是蛋白聚糖基质损失的众所周知的分解代谢罪魁祸首。为了确定Wnt/β-连环蛋白信号传导是否与体内关节软骨中年龄相关的骨关节炎变化相关，我们分析了自发性豚鼠骨关节炎模型中β-连环蛋白的存在和细胞内分布。年轻豚鼠膝关节的健康关节软骨细胞中几乎检测不到b-连环蛋白。相比之下，该蛋白质在老年豚鼠关节中存在的骨关节炎样软骨细胞中高度丰富，并且不仅定位于细胞质中，而且定位于细胞核中，这清楚地反映了激活的Wnt信号传导。这些和其他数据表明，Wnt/β-连环蛋白信号是软骨细胞基质分解代谢作用的强有力刺激物，并且可能是导致年龄相关关节病变中软骨基质过度重塑和降解的机制的一部分。
A fine balance between anabolic and catabolic mechanisms maintains extracellular matrix homeostasis in articular cartilage, and shifts toward degradation are associated with joint conditions such as osteoarthritis. To test the possible involvement, relevance and significance of the Wnt/beta-catenin-signaling pathway in those catabolic shifts, rabbit articular chondrocyte cultures were subjected to experimental activation of beta-catenin signaling by Wnt3A treatment or forced expression of constitutive-active beta-catenin (CA-beta-catenin). Both interventions provoked strong gelatinase activity and stimulated gene expression of matrix metalloprotease-3 and -13 and a disintegrin-like and metalloprotease with thrombospondin motif (ADAMTS)-4 and -5 proteases. Furthermore, Wnt3A treatment additively enhanced the effects of intereukin-1 beta, a well-known catabolic culprit of proteoglycan matrix loss. To determine whether Wnt/beta-catenin signaling is associated with age-associated osteoarthritic changes in articular cartilage in vivo, we analyzed the presence and intracellular distribution of b-catenin in a spontaneous guinea pig osteoarthritis model. Healthy articular chondrocytes in young guinea pig knees contained barely detectable levels of b-catenin. In contrast, the protein was highly abundant in osteoarthritic-like chondrocytes present in older guinea pig joints, and was localized not only in the cytoplasm but also the nucleus, a clear reflection of activated Wnt signaling. These and other data suggest that Wnt/b-catenin signaling is a powerful stimulator of chondrocyte matrix catabolic action and may be part of mechanisms leading to excessive remodeling and degradation of cartilage matrix in age-associated joint pathologies.