Norwegian Center for Stem Cell Research and Institute of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
Stem Cells. 2014 Jun;32(6):1629-35. doi: 10.1002/stem.1642.
The transcription factor SOX9 is believed to be the master regulator of chondrogenesis. SOX8 is another SOX group E transcription factor with a high degree of homology to SOX9. Here, we demonstrate that SOX8 mRNA levels decrease during in vitro dedifferentiation of human articular chondrocytes and increase during chondrogenic differentiation of mesenchymal stromal cells. Knockdown of SOX9 reduced the expression of SOX8, COL2A1, and a range of other chondrogenic molecules. SOX8 knockdown reduced the expression of a large number of overlapping chondrogenic molecules, but not SOX9. Neither siSOX9 nor siSOX8 altered expression of the hypertrophic marker gene COL10A1. siSOX9, but not siSOX8 led to upregulation of hypertrophy associated genes MMP13 and ALPL. Transfection of synthetic SOX5, 6, and 9 mRNA trio upregulated SOX8, COL2A1, and ACAN, but not COL10A1 mRNA. Replacement of synthetic SOX9 by SOX8 in the SOX trio showed similar but lower chondrogenic effect. We conclude that SOX8 expression is regulated by SOX9, and that both together with SOX5 and SOX6 are required as a SOX quartet for transcription of COL2A1 and a large number of other chondrogenic molecules. Neither SOX8 nor SOX9 affect COL10A1 expression, but SOX9 inhibits chondrocyte hypertrophy through inhibition of MMP13 and ALPL expression.
转录因子 SOX9 被认为是软骨形成的主要调节因子。SOX8 是另一种与 SOX9 具有高度同源性的 SOX 族 E 转录因子。在这里，我们证明 SOX8 mRNA 水平在人关节软骨细胞体外去分化过程中降低，在间充质基质细胞软骨分化过程中升高。SOX9 的敲低降低了 SOX8、COL2A1 和一系列其他软骨形成分子的表达。SOX8 的敲低降低了大量重叠的软骨形成分子的表达，但不是 SOX9。siSOX9 和 siSOX8 均未改变肥大标志物基因 COL10A1 的表达。siSOX9 但不是 siSOX8 导致与肥大相关的基因 MMP13 和 ALPL 的表达上调。合成的 SOX5、6 和 9 mRNA 三联体转染上调了 SOX8、COL2A1 和 ACAN，但不上调 COL10A1 mRNA。SOX 三联体中的合成 SOX9 被 SOX8 取代显示出类似但较低的软骨形成效应。我们得出结论，SOX8 的表达受 SOX9 调节，并且 SOX5 和 SOX6 与 SOX8 一起作为 SOX 四重奏，是 COL2A1 和大量其他软骨形成分子转录所必需的。SOX8 和 SOX9 均不影响 COL10A1 的表达，但 SOX9 通过抑制 MMP13 和 ALPL 的表达来抑制软骨细胞肥大。
