Src kinase inhibition promotes the chondrocyte phenotype.
Src kinase inhibition promotes the chondrocyte phenotype.
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DOI：
10.1186/ar2308
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发表时间：
2007
影响因子：
4.9
通讯作者：
Beier F
中科院分区：
文献类型：
--
作者：
Bursell L;Woods A;James CG;Pala D;Leask A;Beier F
软骨细胞的调节分化对于正常骨骼发育和关节软骨的维持都是必不可少的。控制这些事件的细胞内途径尚未完全了解，因此我们在体内或体外调节软骨细胞表型的能力有限。在这里，我们研究了一组突出的细胞内信号传导蛋白，Src家族激酶，在调节软骨细胞表型中发挥的作用。我们发现Src家族激酶林恩在软骨细胞系ATDC 5和高密度单层培养的胚胎小鼠软骨细胞的混合群体中表现出动态表达模式。使用药理学化合物PP 2（4-氨基-5-（4-氯苯基）-7-（叔丁基）吡唑并[3，4-d]嘧啶）抑制Src激酶活性可显著减少原代小鼠软骨细胞的数量。同时，PP 2处理增加了软骨细胞分化的早期标志物（如Sox 9、II型胶原、聚集蛋白聚糖和木糖基转移酶）和晚期标志物（X型胶原、Indian hedgehog和p57）标志物的表达。有趣的是，PP 2抑制Src家族成员林恩，Frk和Hck的表达。它还逆转了单层培养中软骨细胞的形态去分化，诱导软骨细胞变圆，并减少应力纤维形成和粘着斑激酶磷酸化。我们得出结论，Src激酶抑制剂PP 2促进软骨形成基因的表达和形态在单层培养。因此，阻断Src活性的策略可能在软骨的组织工程和在疾病如骨关节炎中维持软骨细胞表型中都是有用的。
Regulated differentiation of chondrocytes is essential for both normal skeletal development and maintenance of articular cartilage. The intracellular pathways that control these events are incompletely understood, and our ability to modulate the chondrocyte phenotype in vivo or in vitro is therefore limited. Here we examine the role played by one prominent group of intracellular signalling proteins, the Src family kinases, in regulating the chondrocyte phenotype. We show that the Src family kinase Lyn exhibits a dynamic expression pattern in the chondrogenic cell line ATDC5 and in a mixed population of embryonic mouse chondrocytes in high-density monolayer culture. Inhibition of Src kinase activity using the pharmacological compound PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine) strongly reduced the number of primary mouse chondrocytes. In parallel, PP2 treatment increased the expression of both early markers (such as Sox9, collagen type II, aggrecan and xylosyltransferases) and late markers (collagen type X, Indian hedgehog and p57) markers of chondrocyte differentiation. Interestingly, PP2 repressed the expression of the Src family members Lyn, Frk and Hck. It also reversed morphological de-differentiation of chondrocytes in monolayer culture and induced rounding of chondrocytes, and reduced stress fibre formation and focal adhesion kinase phosphorylation. We conclude that the Src kinase inhibitor PP2 promotes chondrogenic gene expression and morphology in monolayer culture. Strategies to block Src activity might therefore be useful both in tissue engineering of cartilage and in the maintenance of the chondrocyte phenotype in diseases such as osteoarthritis.
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DOI：
10.1016/0922-3371(90)90079-c
发表时间：
1990-05-01
期刊：
CELL DIFFERENTIATION AND DEVELOPMENT
影响因子：
--
作者：
ATSUMI, T;MIWA, Y;IKAWA, Y
通讯作者：
IKAWA, Y
影响因子：
64.5
作者：
BENYA, PD;PADILLA, SR;NIMNI, ME
通讯作者：
NIMNI, ME
影响因子：
8
作者：
Halawani, D;Mondeh, R;Beier, F
通讯作者：
Beier, F
DOI：
10.1016/j.bbapap.2005.07.027
发表时间：
2005-12-30
影响因子：
3.2
作者：
Chong, YP;Ia, KK;Cheng, HC
通讯作者：
Cheng, HC
影响因子：
--
作者：
James CG;Woods A;Underhill TM;Beier F
通讯作者：
Beier F