CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes
CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes
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DOI：
10.1007/s12079-007-0005-z
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Lyons, Karen M.
中科院分区：
文献类型：
--
作者：
Nishida, Takashi;Kawaki, Harumi;Lyons, Karen M.
通过对 Ccn2 缺陷小鼠的分析表明，基质细胞蛋白 CCN2（结缔组织生长因子；CTGF）是 ECM 组成的重要介质。它们在出生时因软骨内骨化受损引起的并发症而死亡。然而，CCN2 在软骨中介导其作用的机制尚不清楚。我们使用 Ccn2(-/-) 软骨细胞研究了这些机制。 Ccn2(-/-)软骨细胞中II型胶原蛋白和聚集蛋白聚糖的表达减少，证实了ECM产生的缺陷。 Ccn2(-/-) 软骨细胞还表现出 DNA 合成受损和对纤连蛋白的粘附减少。后一种缺陷与α5整合素表达减少有关。此外，CCN2可以与软骨细胞中的整合素α5β1结合，并可以刺激整合素α5的表达增加。与CCN2作为整合素配体的重要作用一致，免疫荧光和蛋白质印迹分析显示，Ccn2(-/-)软骨细胞中粘着斑激酶(FAK)和细胞外信号调节激酶(ERK)1/2磷酸化水平降低。这些发现表明，CCN2 通过以下能力在软骨细胞中发挥主要作用：(1) 调节 ECM 产生和整合素 α 5 表达；(2) 参与整合素；(3) 激活整合素介导的信号通路。
The matricellular protein CCN2 (Connective Tissue Growth Factor; CTGF) is an essential mediator of ECM composition, as revealed through analysis of Ccn2 deficient mice. These die at birth due to complications arising from impaired endochondral ossification. However, the mechanism(s) by which CCN2 mediates its effects in cartilage are unclear. We investigated these mechanisms using Ccn2(-/-) chondrocytes. Expression of type II collagen and aggrecan were decreased in Ccn2(-/-) chondrocytes, confirming a defect in ECM production. Ccn2(-/-) chondrocytes also exhibited impaired DNA synthesis and reduced adhesion to fibronectin. This latter defect is associated with decreased expression of alpha 5 integrin. Moreover, CCN2 can bind to integrin alpha 5 beta 1 in chondrocytes and can stimulate increased expression of integrin alpha 5. Consistent with an essential role for CCN2 as a ligand for integrins, immuno-fluorescence and Western blot analysis revealed that levels of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK)1/2 phosphorylation were reduced in Ccn2(-/-) chondrocytes. These findings argue that CCN2 exerts major effects in chondrocytes through its ability to (1) regulate ECM production and integrin alpha 5 expression, (2) engage integrins and (3) activate integrin-mediated signaling pathways.