Research Paper|Volume 13, Issue 8|pp 11336—11351

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

Yan Deng^1,^2,^3,^4,^5,^6,^7,⁸, Ling Li^7,⁸, Jia-Hui Zhu^7,⁸, Pei-Pei Li^7,⁸, Yi-Xuan Deng^7,⁸, Hong-Hong Luo^7,⁸, Yuan-Yuan Yang^7,⁸, Bai-Cheng He^7,⁸, Yuxi Su^1,^2,^3,^4,^5,⁶

¹Department of Orthopedics, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
²Chongqing Key Laboratory of Pediatrics, Chongqing Medical University, Chongqing 400014, China
³Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China
⁴National Clinical Research Center for Child Health and Disorders, Chongqing Medical University, Chongqing 400014, China
⁵China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Medical University, Chongqing 400014, China
⁶Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
⁷Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
⁸Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China

* Equal contribution

Received: August 18, 2020Accepted: January 21, 2021Published: April 4, 2021

https://doi.org/10.18632/aging.202825

Copyright: © 2021 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.