Takada Ichiro, Kouzmenko Alexander P, Kato Shigeaki
University of Tokyo, Institute of Molecular and Cellular Biosciences, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-0032 Japan.
Expert Opin Ther Targets. 2009 May;13(5):593-603. doi: 10.1517/14728220902915310.
Osteoblasts and adipocytes differentiate from a common precursor, the pluripotent mesenchymal stem cell (MSC) found in bone marrow (BMSC) and adipose tissue (AD-MSC). Numerous transcription factors and multiple extracellular and intracellular signals regulating adipogenesis and osteoblastogenesis have been identified and analyzed. Significantly, inducers of differentiation towards one lineage may inhibit cell differentiation into an alternative lineage. For example, the canonical Wnt/beta-catenin pathway induces osteoblastogenesis and inhibits adipogenesis, whereas the peroxisome proliferator activated receptor-gamma (PPAR-gamma) is a prime inducer of adipogenesis and, as shown in recent studies, inhibits osteoblastogenesis. We have identified two signaling pathways that switch the cell fate decision from adipocytes to osteoblasts by suppressing the transactivation function of PPAR-gamma. In the first pathway, the TNF-alpha- or IL-1-induced TAK1/TAB1/NIK signaling cascade attenuates PPAR-gamma-mediated adipogenesis by inhibiting the binding of PPAR-gamma to the DNA response element. The second is the noncanonical Wnt pathway through the CaMKII-TAK1/TAB2-NLK (nemo-like kinase) signaling cascade. Specifically, Wnt-5a-induced phosphorylation of NLK triggers formation of a complex with the histone methyltransferase SETDB1 (SET domain, bifurcated 1) that represses PPAR-gamma transactivation through histone H3-K9 methylation at the target genes. Thus, two signaling cascades promote osteoblastic differentiation from MSC through two distinct modes of PPAR-gamma transrepression.
成骨细胞和脂肪细胞由共同的前体细胞分化而来，这种多能间充质干细胞（MSC）存在于骨髓（BMSC）和脂肪组织（AD-MSC）中。众多转录因子以及多种调节脂肪生成和成骨细胞生成的细胞外和细胞内信号已被识别和分析。重要的是，一种谱系分化的诱导剂可能会抑制细胞向另一种谱系的分化。例如，经典的Wnt/β-连环蛋白信号通路诱导成骨细胞生成并抑制脂肪生成，而过氧化物酶体增殖物激活受体γ（PPAR-γ）是脂肪生成的主要诱导剂，并且如最近的研究所表明的，它会抑制成骨细胞生成。我们已经识别出两条信号通路，它们通过抑制PPAR-γ的反式激活功能来将细胞命运决定从脂肪细胞转变为成骨细胞。在第一条通路中，TNF-α或IL-1诱导的TAK1/TAB1/NIK信号级联通过抑制PPAR-γ与DNA反应元件的结合来减弱PPAR-γ介导的脂肪生成。第二条是通过CaMKII-TAK1/TAB2-NLK（类Nemo样激酶）信号级联的非经典Wnt信号通路。具体而言，Wnt-5a诱导的NLK磷酸化触发了与组蛋白甲基转移酶SETDB1（SET结构域，分叉1）形成复合物，该复合物通过在靶基因处的组蛋白H3-K9甲基化来抑制PPAR-γ的反式激活。因此，两条信号级联通过两种不同的PPAR-γ反式抑制模式促进了间充质干细胞向成骨细胞的分化。
