PIASxβ is a key regulator of osterix transcriptional activity and matrix mineralization in osteoblasts
PIASxβ is a key regulator of osterix transcriptional activity and matrix mineralization in osteoblasts
复制标题
DOI：
10.1242/jcs.005090
复制
发表时间：
2007-08-01
影响因子：
4
通讯作者：
Kawashima, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ali, Md. Moksed;Yoshizawa, Tatsuya;Kawashima, Hiroyuki
我们最近报道了拉伸应力诱导小鼠颅骨缝合线成骨细胞分化和成骨。利用该实验系统，我们鉴定出PIASx β， Pias2的剪接异构体，是受拉伸应力上调程度最高的基因之一。进一步的细胞培养研究表明，这种上调是短暂的，并伴随着其他分化标志物（包括osterix）的上调，而Runx2的表达不受影响。Runx2和osterix是控制成骨细胞分化的两个主蛋白，其中Runx2位于osterix的上游。通过小干扰RNA （siRNA）靶向敲低PIASx β显著抑制成骨细胞分化和基质矿化，而PIASx β的短暂过表达则产生完全相反的效果。无论PIASx β的表达水平如何，Runx2的表达保持不变。报告者实验表明，osterix增强了其自身的启动子活性，PIASx β进一步刺激了启动子活性，而其summoylation缺陷突变体则没有。当NFATc1和NFATc3与PIASx β共转染时，还能增加骨组织的转录活性。由于osterix没有一致的sumoylation基序，其他蛋白可能参与PIASx β介导的激活，NFAT蛋白可能是这些靶标之一。这项研究提供了第一个证据，证明PIASx β是成骨细胞分化和基质矿化不可或缺的，并且该信号分子位于Runx2和osterix之间。
We recently reported that tensile stress induces osteoblast differentiation and osteogenesis in the mouse calvarial suture in vitro. Using this experimental system, we identified PIASx beta, a splice isoform of Pias2, as one of the genes most highly upregulated by tensile stress. Further study using cell culture revealed that this upregulation was transient and was accompanied by upregulation of other differentiation markers, including osterix, whereas expression of Runx2 was unaffected. Runx2 and osterix are the two master proteins controlling osteoblast differentiation, with Runx2 being upstream of osterix. Targeted knockdown of PIASx beta by small interfering RNA (siRNA) markedly suppressed osteoblastic differentiation and matrix mineralization, whereas transient overexpression of PIASx beta caused the exact opposite effects. Regardless of PIASx beta expression level, Runx2 expression remained constant. Reporter assays demonstrated that osterix enhanced its own promoter activity, which was further stimulated by PIASx beta but not by its sumoylation-defective mutant. NFATc1 and NFATc3 additionally increased osterix transcriptional activity when co-transfected with PIASx beta. Because osterix has no consensus motif for sumoylation, other proteins are probably involved in the PIASx beta-mediated activation and NFAT proteins may be among such targets. This study provides the first line of evidence that PIASx beta is indispensable for osteoblast differentiation and matrix mineralization, and that this signaling molecule is located between Runx2 and osterix.