Homeobox protein Msx2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts
Homeobox protein Msx2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts
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DOI：
10.1128/mcb.24.8.3460-3472.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Kawashima, H
中科院分区：
文献类型：
--
作者：
Yoshizawa, T;Takizawa, F;Kawashima, H
韧带和肌腱由坚韧而柔韧的结缔组织组成。然而，由于缺乏特定的标记物和细胞系，人们对韧带和肌腱中细胞的精确特征知之甚少。我们最近报道了一种牙周膜细胞系PDL-L2，其Runx2/Osf2转录活性受到抑制，并且不能形成矿化结节。目前的研究表明，同源异型盒蛋白Msx2是抑制这两种功能的关键因素。Msx2与Runx2/Osf2共定位并协同抑制其活性，与另一辅阻遏物TLE1作为复合物作用以募集组蛋白去乙酰化酶1活性。逆转录-PCR和原位杂交结果显示，Msx2在牙周膜和肌腱细胞中的表达高于成骨细胞。PDL-L2细胞中Msx2表达的稳定降低诱导成骨细胞分化，从而引起基质矿化。相反，MC3T3-E1细胞中稳定的、强制的Msx2表达阻止了成骨细胞分化和基质矿化。骨形态发生蛋白2抑制msx 2诱导的成骨细胞分化。此外，Msx2在后纵韧带骨化患者的受累区域以症状和钙化依赖性方式下调。我们的研究结果表明Msx2在防止韧带和肌腱矿化方面起着核心作用。
Ligaments and tendons are comprised of tough yet flexible connective tissue. Little is known, however, about the precise characteristics of the cells in ligaments and tendons due to the absence of specific markers and cell lines. We recently reported a periodontal ligament cell line, PDL-L2, with suppressed Runx2/Osf2 transcriptional activity and an inability to form mineralized nodules. The present study demonstrates that the homeobox protein Msx2 is a key factor in suppressing those two functions. Msx2 colocalizes with Runx2/Osf2 and suppresses its activity cooperatively, acting with another corepressor, TLE1, as a complex to recruit histone deacetylase 1 activity. Reverse transcription-PCR and in situ hybridization demonstrated that Msx2 expression is higher in periodontal ligament and tendon cells than in osteoblasts. Stable reduction of Msx2 expression in PDL-L2 cells induces osteoblastic differentiation, thereby causing matrix mineralization. Conversely, stable, forced Msx2 expression in MC3T3-E1 cells prevented osteoblast differentiation and matrix mineralization. Msx2-induced suppression of osteoblast differentiation was repressed by bone morphogenetic protein 2. In addition, Msx2 was downregulated in a symptom- and calcification-dependent manner at the affected region in patients with ossification of the posterior longitudinal ligament. Our findings indicate that Msx2 plays a central role in preventing ligaments and tendons from mineralizing.