Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase
Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase
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DOI：
10.1074/jbc.275.13.9645
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发表时间：
2000-03-31
影响因子：
4.8
通讯作者：
Pittenger, MF
中科院分区：
文献类型：
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作者：
Jaiswal, RK;Jaiswal, N;Pittenger, MF
成人间充质干细胞是原代多能细胞，当在适当条件下刺激时，能够分化成骨细胞、软骨细胞和脂肪细胞谱系。为了表征调控成骨分化的分子机制，我们研究了丝裂原活化蛋白激酶家族成员ERK、JNK和p38的贡献。用成骨补充剂处理这些干细胞导致ERK活化的持续阶段，从第7天到第11天，这与分化一致，然后降低到基础水平。JNK的激活发生在成骨分化过程的晚得多的时间（第13天至第17天）。这种JNK激活与细胞外基质合成和钙沉积增加有关，这是骨形成的两个标志。ERK信号通路的特异性抑制剂PD 98059抑制ERK活化，以剂量依赖性方式阻断成骨分化，与用显性负性形式的MAP激酶（MEK-1）转染一样，显著地，成骨分化的阻断导致干细胞的成脂分化和脂肪特异性mRNA过氧化物酶体增殖物的表达。活化受体γ 2、aP 2和脂蛋白脂肪酶。这些观察结果提供了一个潜在的机制，涉及MAP激酶激活成骨分化的成体干细胞，并建议承诺的hMSCs成骨或成脂谱系是由ERK的激活或抑制，分别。
Adult human mesenchymal stem cells are primary, multipotent cells capable of differentiating to osteocytic, chondrocytic, and adipocytic lineages when stimulated under appropriate conditions. To characterize the molecular mechanisms that regulate osteogenic differentiation, we examined the contribution of mitogen-activated protein kinase family members, ERK, JNK, and p38, Treatment of these stem cells with osteogenic supplements resulted in a sustained phase of ERK activation from day 7 to day 11 that coincided with differentiation, before decreasing to basal levels. Activation of JNK occurred much later (day 13 to day 17) in the osteogenic differentiation process. This JNK activation was associated with extracellular matrix synthesis and increased calcium deposition, the two hallmarks of bone formation. Inhibition of ERK activation by PD98059, a specific inhibitor of the ERK signaling pathway, blocked the osteogenic differentiation in a dose-dependent manner, as did transfection with a dominant negative form of MAP kinase kinase (MEK-1), Significantly, the blockage of osteogenic differentiation resulted in the adipogenic differentiation of the stem cells and the expression of adipose-specific mRNAs peroxisome proliferator-activated receptor gamma 2, aP2, and lipoprotein lipase. These observations provide a potential mechanism involving MAP kinase activation in osteogenic differentiation of adult stem cells and suggest that commitment of hMSCs into osteogenic or adipogenic lineages is governed by activation or inhibition of ERK, respectively.