COX-2 通过 TGF-β1/p38 信号通路促进间充质干细胞中 BMP9 的成骨潜能。

COX-2 promotes the osteogenic potential of BMP9 through TGF-β1/p38 signaling in mesenchymal stem cells.

机构信息

Department of Orthopedics, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.

Chongqing Key Laboratory of Pediatrics, Chongqing Medical University, Chongqing 400014, China.

出版信息

Aging (Albany NY). 2021 Apr 4;13(8):11336-11351. doi: 10.18632/aging.202825.

DOI:10.18632/aging.202825

PMID:33833129

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8109063/

Abstract

This study investigated the effects of transforming growth factor-β1 (TGF-β1) and cyclooxygenase-2 (COX-2) on bone morphogenetic protein 9 (BMP9) in mesenchymal stem cells (MSCs). We found that BMP9 increased mRNA levels of TGF-β1 and COX-2 in C3H10T1/2 cells. BMP9-induced osteogenic markers were enhanced by TGF-β1 and reduced by TGF-βRI-specific inhibitor LY364947. BMP9 increased level of p-Smad2/3, which were either enhanced or reduced by COX-2 and its inhibitor NS398. BMP9-induced osteogenic markers were decreased by NS398 and it was partially reversed by TGF-β1. COX-2 increased BMP9-induced osteogenic marker levels, which almost abolished by LY364947. BMP9-induced bone formation was enhanced by TGF-β1 but reduced by silencing TGF-β1 or COX-2. BMP9's osteogenic ability was inhibited by silencing COX-2 but partially reversed by TGF-β1. TGF-β1 and COX-2 enhanced activation of p38 signaling, which was induced by BMP9 and reduced by LY364947. The ability of TGF-β1 to increase the BMP9-induced osteogenic markers was reduced by p38-specific inhibitor, while BMP9-induced TGF-β1 expression was reduced by NS398, but enhanced by COX-2. Furthermore, CREB interacted with Smad1/5/8 to regulate TGF-β1 expression in MSCs. These findings suggest that COX-2 overexpression leads to increase BMP9's osteogenic ability, resulting from TGF-β1 upregulation which then activates p38 signaling in MSCs.

摘要

这项研究探讨了转化生长因子-β1（TGF-β1）和环氧化酶-2（COX-2）对间充质干细胞（MSCs）中骨形态发生蛋白 9（BMP9）的影响。我们发现 BMP9 增加了 C3H10T1/2 细胞中 TGF-β1 和 COX-2 的 mRNA 水平。TGF-β1 和 TGF-βRI 特异性抑制剂 LY364947 增强了 BMP9 诱导的成骨标志物。BMP9 增加了 p-Smad2/3 的水平，COX-2 和其抑制剂 NS398 要么增强要么减少 p-Smad2/3 的水平。BMP9 诱导的成骨标志物被 NS398 降低，而被 TGF-β1 部分逆转。COX-2 增加了 BMP9 诱导的成骨标志物水平，而 LY364947 几乎消除了这一作用。BMP9 诱导的骨形成被 TGF-β1 增强，但被沉默 TGF-β1 或 COX-2 减弱。BMP9 的成骨能力被沉默 COX-2 抑制，但被 TGF-β1 部分逆转。TGF-β1 和 COX-2 增强了 BMP9 诱导的 p38 信号的激活，而 LY364947 则降低了 p38 信号的激活。TGF-β1 增加 BMP9 诱导的成骨标志物的能力被 p38 特异性抑制剂降低，而 BMP9 诱导的 TGF-β1 表达被 NS398 降低，但被 COX-2 增强。此外，CREB 与 Smad1/5/8 相互作用，调节 MSCs 中的 TGF-β1 表达。这些发现表明，COX-2 的过表达导致 BMP9 的成骨能力增加，这是由于 TGF-β1 的上调，继而激活了 MSCs 中的 p38 信号。