All-trans retinoic acid and COX-2 cross-talk to regulate BMP9-induced osteogenic differentiation via Wnt/beta-catenin in mesenchymal stem cells
All-trans retinoic acid and COX-2 cross-talk to regulate BMP9-induced osteogenic differentiation via Wnt/beta-catenin in mesenchymal stem cells
复制标题
全反式视黄酸和 COX-2 串扰通过 Wnt/β-catenin 调节间充质干细胞中 BMP9 诱导的成骨分化
DOI：
10.1016/j.biopha.2019.109279
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发表时间：
2019
影响因子：
7.5
通讯作者：
He Bai Cheng
中科院分区：
文献类型：
--
作者：
Wang Han;Hu Ying;He Fang;Ling Li;Li Pei Pei;Deng Yan;Li Fu Shu;Wu Ke;He Bai Cheng
考克斯-2特异性抑制剂可延缓骨折愈合，降低骨髓基质细胞的成骨潜能，已被广泛应用。然而，如何预防考克斯-2抑制剂的这些副作用仍是未知数。本研究以骨形成蛋白9（BMP 9）诱导的成骨分化为模型，通过体内外实验研究全反式维甲酸（ATRA）能否改善考克斯-2特异性抑制剂对骨代谢的不利影响，并探讨其可能的作用机制。结果表明，ATRA可增强BMP 9诱导碱性磷酸酶（ALP）和矿化等成骨标志物生成的能力，而RA受体α（RARa）抑制剂则可逆转其作用。考克斯-2特异性抑制剂（NS 398）可降低BMP 9诱导的成骨标志物，ATRA几乎消除了NS 398的抑制作用。BMP 9上调β-catenin的蛋白水平并促进其向细胞核的转位，两者均被NS 398所抑制。ATRA可明显减弱NS 398对BMP 9诱导的β-catenin表达的抑制作用。外源性RXR α明显改善了沉默考克斯-2对BMP 9诱导异位成骨的抑制作用。NS 398降低磷酸化CREB的水平，ATRA几乎可以逆转这一作用。此外，RXRa与磷酸化CREB直接相互作用，并在β-catenin启动子区募集。因此，我们认为ATRA可能通过部分增强Wnt/β-catenin通路的激活，逆转考克斯-2抑制剂对骨代谢的副作用。
COX-2 specific inhibitor, which has been widely used, can delay bone fracture healing and reduce osteogenic potential of bone marrow stromal cells. However, it remains unknown how to prevent these side-effects of COX-2 inhibitor. In this study, we introduced BMP9-induced osteogenic differentiation as model to evaluate whether all-trans retinoic acid (ATRA) could ameliorate these adverse effects of COX-2 specific inhibitor on bone metabolism with in vitro and in vivo experiments, and uncover the possible mechanism underlying this process. Results showed that ATRA enhanced the potential of BMP9 to induce the osteogenic markers, such as alkaline phosphates (ALP) and mineralization; but retinoic acid receptor a (RARa) inhibitor showed the reversal effects. COX-2 specific inhibitor (NS398) reduced the osteogenic markers induced by BMP9, and ATRA almost eliminated the inhibitory effect of NS398. BMP9 up-regulated the protein level of β-catenin and promoted it translocate to nucleus, and both were reduced by NS398. On the contrary, ATRA notablely attenuated the inhibitory effect of NS398 on BMP9-increased β-catenin. Exogenous RXRa obviously ameliorated the inhibitory effect of silencing COX-2 on ectopic bone formation induced by BMP9. NS398 reduced the level of phosphorylated CREB, which was almost reversed by ATRA. Besides, RXRa interacted with phosphorylated CREB directly and both were recruited at β-catenin promoter region. Thus, we demonstrated that ATRA may reverse the side-effects of COX-2 inhibitor on bone metabolism through increasing the activation of Wnt/β-catenin pathway partly.