Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes
Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes
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DOI：
10.1007/s00774-012-0385-x
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Yoneda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Hisada, Kunihiro;Hata, Kenji;Yoneda, Toshiyuki
有证据表明，间充质干细胞（MSCs）的成骨细胞和脂肪细胞之间的平衡是由几种激素，生长因子，及其下游信号级联调节。以往的研究表明，视黄酸（RA）在成骨细胞和脂肪形成中起作用。然而，目前还不清楚RA是否调节骨髓间充质干细胞向成骨细胞和脂肪细胞的承诺。在这项研究中，我们研究了RA在使用C3 H10 T1/2细胞系的MSC分化中的作用。RA刺激碱性磷酸酶（ALP）的活性和表达，并上调ALP基因启动子的活性。骨形态发生蛋白2（BMP 2）和由此产生的Smad信号进一步增强RA的作用。此外，Runx 2和Msx 2的过度表达，骨形成和BMP 2依赖性成骨细胞的关键转录因子，增强RA依赖性ALP活性。鉴于这些发现，RA可能通过BMP 2-Smad-Runx 2/Msx 2途径刺激成骨细胞分化。与此相反，RA显著抑制BMP 2诱导的脂肪细胞分化，抑制过氧化物酶体增殖物激活受体γ（PPAR γ），CCAAT/增强子结合蛋白（C/EBP）α和C/EBP δ的表达，并抑制C/EBP β，C/EBP δ和PPAR γ的脂肪形成功能。总之，我们的数据表明，RA调节承诺的骨髓间充质干细胞成骨细胞和脂肪细胞通过控制转录调节因子。
Evidence indicates that the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells (MSCs) is regulated by several hormones, growth factors, and their downstream signaling cascades. Previous studies suggest that retinoic acid (RA) plays a role in osteoblastogenesis and adipogenesis. However, it is unknown whether RA regulates commitment of MSCs into osteoblasts and adipocytes. In this study, we investigated the role of RA in differentiation of MSCs using the C3H10T1/2 cell line. RA stimulated activity and expression of alkaline phosphatase (ALP) and upregulated activity of the ALP gene promoter. The effects of RA were further enhanced by bone morphogenetic protein 2 (BMP2) and resultant Smad signaling. Furthermore, overexpression of Runx2 and Msx2, critical transcription factors for bone formation and BMP2-dependent osteoblastogenesis, enhanced RA-dependent ALP activity. In view of these findings, RA likely stimulates osteoblast differentiation through the BMP2-Smad-Runx2/Msx2 pathway. In contrast, RA markedly inhibited BMP2-induced adipocyte differentiation, suppressing expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma), CCAAT/enhancer-binding protein (C/EBP)alpha and C/EBP delta, and inhibiting adipogenic function of C/EBP beta, C/EBP delta, and PPAR gamma. In conclusion, our data suggest that RA regulates commitment of MSCs into osteoblasts and adipocytes by controlling transcriptional regulators.