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All-trans retinoic acid can antagonize osteoblastogenesis induced by different BMPs irrespective of their dimerization types and dose-efficiencies

Authors Liu Y, Ma X, Guo J, Lin Z, Zhou M, Bi W, Liu J, Wang J, Lu H, Wu G

Received 25 June 2018

Accepted for publication 3 August 2018

Published 10 October 2018 Volume 2018:12 Pages 3419—3430

DOI https://doi.org/10.2147/DDDT.S178190

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Cristiana Tanase


Yi Liu,1,* Xiaoqing Ma,2,* Jing Guo,1 Zhen Lin,3 Miao Zhou,1 Wenjuan Bi,4 Jinsong Liu,5 Jingxiao Wang,6 Haiping Lu,7,* Gang Wu8,*

1Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510140, China; 2Shanghai Xuhui District Dental Center, Shanghai 200032, China; 3Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; 4College of Stomatology, North China University of Science and Technology, Tangshan 063000, China; 5School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325000, China; 6The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China; 7School of Stomatology, Zhejiang Chinese Medical University, Hangzhou 310053, China; 8Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, 1081LA Amsterdam, the Netherlands

*These authors contributed equally to this work

Introduction: Alcoholism can lead to low mineral density, compromised regenerative bone capacity and delayed osteointegration of dental implants. This may be partially attributed to the inhibitive effect of all-trans retinoic acid (ATRA), a metabolite of alcohol, on osteoblastogenesis. Our previous studies demonstrated that heterodimeric bone morphogenetic protein 2/7 (BMP2/7) was a more potent BMP than homodimeric BMP2 or BMP7, and could antagonize the inhibitive effect of ATRA to rescue osteoblastogenesis.
Materials and methods: In this study, we compared the effectiveness of BMP2/7, BMP2 and BMP7 in restoring osteoblastogenesis of murine preosteoblasts upon inhibition with 1 µM ATRA, and we further analyzed the potential mechanisms. We measured the following parameters: cell viability, ALP, OCN, mineralization, the expression of osteogenic differentiation marker genes (Collagen I, ALP and OCN) and the expression of BMP signaling key genes (Dlx5, Runx2, Osterix and Smad1).
Results: BMP2/7 treatment alone induced significantly higher osteoblastogenesis compared to BMP2 and BMP7. When cells were treated by ATRA, BMP2/7 was superior only in rescuing cell viability and ALP activity, compared to BMP2 or BMP7. However, BMP2/7 was not superior to BMP2 or BMP7 in restoring OCN expression and extracellular mineralized nodules, or in rescuing expression of two key osteogenic genes, Dlx5 and Runx2. Irrespective of their dimeric types or potency, the selected BMPs could antagonize the inhibitory effect of ATRA on osteoblastogenesis.
Conclusion: The presence of ATRA, BMP2/7 still induced significantly higher cell viability and early differentiation than the homodimers. However, ATRA significantly attenuated the advantages of BMP2/7 in inducing late and final osteoblastogenic differentiation over the homodimers.

Keywords: heterodimeric, homodimeric, bone morphogenetic protein, osteoblastogenesis, all-trans retinoic acid

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