p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells
p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells
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DOI：
10.1006/excr.1999.4535
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发表时间：
1999-08-01
影响因子：
3.7
通讯作者：
Makishima, F
中科院分区：
文献类型：
--
作者：
Nakamura, K;Shirai, T;Makishima, F
转化生长因子-β（TG; F-P）超家族的研究主要集中在Smad蛋白上，但对丝裂原活化蛋白（MAP）激酶级联反应关注较少。在小鼠软骨形成细胞系ATDC 5中，通过诱导细胞凝聚和随后的软骨结节形成，完全促进软骨形成反应的早期阶段。我们研究了三种主要类型的MAP激酶中的哪一种（如果有的话）在GDF-5诱导的软骨形成的促进中起功能作用，GDF-5诱导p38 MAP激酶和细胞外信号调节激酶（ERK）的磷酸化，但不诱导c-Jun N-末端激酶（JNK）的磷酸化。BMP-2和TGF-β 1也可诱导p38 MAP激酶的磷酸化。p38和p38 β MAP激酶的抑制剂SB 202190显示出对软骨结节形成的完全抑制，但未能影响由GDF-5诱导的碱性磷酸酶（ALP）活性。II型胶原基因的表达（脊椎动物中软骨形成的标志）也由GDF-5处理诱导并被SB 202190强烈抑制。尽管MAP/ERK激酶抑制剂PD 98059抑制GDF-5对ERK的快速磷酸化，但它既不抑制ALP活性，也不抑制GDF-5诱导的软骨结节形成。这些结果强烈表明，p38 MAP激酶级联参与GDF-5信号传导途径，并且p38 MAP激酶途径的作用在较长时期内是促进ATDC 5细胞中软骨形成所必需的，（C）1999 Academic Press。
Recent studies of intracellular signal transduction mechanisms for the transforming growth factor-beta (TG;F-P) superfamily have focused on Smad proteins, but have paid little attention to mitogen-activated protein (MAP) kinase cascades, Here we demonstrate that growth/differentiation factor-5 (GDF-5), but neither bone morphogenetic protein-2 (BMP-2) nor TGF-beta 1, fully promotes the early phase of the chondrogenic response by inducing cellular condensation followed by cartilage nodule formation in a mouse chondrogenic cell line, ATDC5. We investigated which, if any, of the three major types of MAP kinase plays a functional role in the promotion of chondrogenesis induced by GDF-5, GDF-5 induced phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase (ERK) but not that of c-Jun N-terminal kinase (JNK). The phosphorylation of p38 MAP kinase was also induced by BMP-2 and TGF-beta 1. An inhibitor of p38 and p38 beta MAP kinase, SB202190, showed complete inhibition of cartilage nodule formation but failed to affect alkaline phosphatase (ALP) activity induced by GDF-5, Expression of the type II collagen gene, a hallmark of chondrogenesis in vertebrates, was also induced by GDF-5 treatment and strongly suppressed by SB202190, On the other hand, although an inhibitor of MAP/ERK kinase, PD98059, inhibited the rapid phosphorylation of ERK by GDF-5, it inhibited neither ALP activity nor cartilage nodule formation induced by GDF-5. These results strongly suggest that the p38 MAP kinase cascade is involved in GDF-5 signaling pathways and that a role of the p38 MAP kinase pathway is necessary over a longer period to promote chondrogenesis in ATDC5 cells, (C) 1999 Academic Press.