Molecular and Cellular Pharmacology Graduate Program, Leonard M Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
PLoS One. 2011;6(10):e26769. doi: 10.1371/journal.pone.0026769. Epub 2011 Oct 26.
Sox9 is an SRY-related transcription factor required for expression of cartilaginous genes in the developing skeletal system and heart valve structures. In contrast to positively regulating cartilaginous matrix, Sox9 also negatively regulates matrix mineralization associated with bone formation. While the transcriptional activation of Sox9 target genes during chondrogenesis has been characterized, the mechanisms by which Sox9 represses osteogenic processes are not so clear. Using ChIP-on-chip and luciferase assays we show that Sox9 binds and represses transactivation of the osteogenic glycoprotein Spp1. In addition, Sox9 knockdown in post natal mouse heart valve explants and rib chondrocyte cultures promotes Spp1 expression and matrix mineralization, while attenuating expression of cartilage genes Type II Collagen and Cartilage Link Protein. Further, we show that Spp1 is required for matrix mineralization induced by Sox9 knockdown. These studies provide insights into the molecular mechanisms by which Sox9 prevents pathologic matrix mineralization in tissues that must remain cartilaginous.
Sox9 是一种与 SRY 相关的转录因子，对于发育中的骨骼系统和心脏瓣膜结构中软骨基因的表达是必需的。与正向调控软骨基质不同，Sox9 还负向调控与骨形成相关的基质矿化。虽然 Sox9 靶基因在软骨发生过程中的转录激活已被描述，但 Sox9 抑制成骨过程的机制尚不清楚。通过 ChIP-on-chip 和荧光素酶检测，我们发现 Sox9 结合并抑制骨形成糖蛋白 Spp1 的转录激活。此外，在出生后小鼠心脏瓣膜外植体和肋软骨细胞培养物中敲低 Sox9 会促进 Spp1 的表达和基质矿化，同时减弱软骨基因 II 型胶原和软骨连接蛋白的表达。此外，我们发现 Spp1 是 Sox9 敲低诱导的基质矿化所必需的。这些研究为 Sox9 防止必需保持软骨特性的组织中病理性基质矿化的分子机制提供了见解。
