Transcriptional coactivator PGC-1α regulates chondrogenesis via association with Sox9
Transcriptional coactivator PGC-1α regulates chondrogenesis via association with Sox9
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DOI：
10.1073/pnas.0407510102
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发表时间：
2005-02-15
影响因子：
11.1
通讯作者：
Asahara, H
中科院分区：
文献类型：
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作者：
Kawakami, Y;Tsuda, M;Asahara, H
软骨发生是多潜能间充质干细胞（MSC）向软骨细胞分化的多步骤途径。转录因子Sox 9（SRY相关高迁移率族基因9）调节软骨细胞分化和软骨特异性基因表达，如Col 2a 1（II型胶原α 1）。然而，Sox 9表达不仅在软骨形成组织中检测到，而且在非软骨形成组织中也检测到，这表明存在Sox 9控制软骨形成和软骨形成基因表达所需的分子伴侣。在这里，我们报告识别过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）作为软骨形成过程中Sox 9的辅激活因子。PGC-1 α的表达在小鼠胚胎肢体发育和人MSC培养的软骨形成过程中的软骨形成部位被诱导。PGC-1 α直接与Sox 9相互作用，并促进Sox 9依赖的转录活性，表明PGC-1 α作为Sox 9的转录辅激活因子。与这一发现相一致的是，在软骨形成过程中，通过小干扰RNA破坏MSC中的PGC-1a抑制Col 2a 1表达。此外，PGC-1 α和Sox 9的过度表达诱导软骨形成基因的表达，包括Col 2a 1，随后在MSC和发育中的鸡肢中进行软骨形成。总之，我们的研究结果表明软骨形成的转录机制是由PGC-1 α协调的。
Chondrogenesis is a multistep pathway in which multipotential mesenchymal stem cells (MSC) differentiate into chondrocytes. The transcription factor Sox9 (SRY-related high mobility group-Box gene 9) regulates chondrocyte differentiation and cartilage-specific expression of genes, such as Col2a1 (collagen type II alpha1). However, Sox9 expression is detected not only in chondrogenic tissue but also in nonchondrogenic tissues, suggesting the existence of a molecular partner(s) required for Sox9 to control chondrogenesis and chondrogenic gene expression. Here, we report identification of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) as a coactivator for Sox9 during chondrogenesis. Expression of PGC-1alpha is induced at chondrogenesis sites during mouse embryonic limb development and during chondrogenesis in human MSC cultures. PGC-1alpha directly interacts with Sox9 and promotes Sox9-dependent transcriptional activity, suggesting that PGC-1alpha acts as a transcriptional coactivator for Sox9. Consistent with this finding, PGC-1a disruption in MSC by small interfering RNA inhibits Col2a1 expression during chondrogenesis. Furthermore, overexpression of both PGC-1alpha and Sox9 induced expression of chondrogenic genes, including Col2a1, followed by chondrogenesis in the MSC and developing chick limb. Together, our results suggest a transcriptional mechanism for chondrogenesis that is coordinated by PGC-1alpha.