Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts
Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts
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DOI：
10.1196/annals.1402.034
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发表时间：
2007-01-01
期刊：
影响因子：
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通讯作者：
Kato, Shigeaki
中科院分区：
文献类型：
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作者：
Takada, Ichiro;Suzawa, Miyuki;Kato, Shigeaki
成骨细胞和脂肪细胞是由普通的多效间充质干细胞在转录调控下通过多种因子和多种细胞内信号传导分化而来。然而，尽管过氧化物酶体增殖物激活受体γ（PPAR-T）已被公认为脂肪形成的主要诱导剂，但决定骨髓间充质干细胞命运的细胞信号传导因子仍在很大程度上尚未被发现。在这里，我们描述了两个信号通路，诱导细胞的命运决定成骨细胞从脂肪细胞。一种信号传导是由TNF-α和IL-1激活的TAK 1/TAB 1/NIK级联，并且激活的NF-κ B阻断了PPAR-γ的DNA结合，减弱了激活的PPAR介导的脂肪生成。第二个信号传导是通过CaMKII-TAK 1/TAB 2-NLK的非经典Wnt通路。非经典Wnt配体（Wnt-5a）激活的NLK通过组蛋白甲基转移酶反式抑制PPAR反式激活，SETDB 1 Wnt-5a诱导NLK磷酸化，导致形成辅阻遏物复合物，通过组蛋白H3-K9甲基化使PPAR功能失活。因此，两个信号通路导致成骨细胞谱系决定从间充质干细胞通过两种不同的模式的过氧化物酶体增殖物激活物受体反式阻遏。
Osteoblasts and adipocytes differentiate from common pleiotropic mesenchymal stem cells under transcriptional controls by numerous factors and multiple intracellular signalings. However, cellular signaling factors that determine cell fates of mensenchymal stem cells in bone marrow remain to be largely uncovered, though peroxisome proliferator-activated receptor-gamma (PPAR-T) is well established as a prime inducer of adipogenesis. Here, we describe two signaling pathways that induce the cell fate decision into osteoblasts from adipocytes. One signaling is a TAK1/TAB1/NIK cascade activated by TNF-alpha and IL-1, and the activated NF-kappa B blocked the DNA binding of PPAR-gamma, attenuating the activated PPAR-mediated adipogenesis. The second signaling is the noncanonical Wnt pathway through CaMKII-TAK1/TAB2-NLK. Activated NLK by a noncanonical Wnt ligand (Wnt-5a) transrepresses PPAR transactivation through a histone methyltransferase, SETDB1 Wnt-5a induces phosphorylation of NLK, leading to the formation of a corepressor complex that inactivates PPAR function through histone H3-K9 methylation. Thus, two signaling pathways lead to an osteoblastic cell lineage decision from mesenchymal stem cells through two distinct modes of PPAR transrepression.