The antagonist of retinoic acid receptor α, ER-50891 antagonizes the inhibitive effect of all-trans retinoic acid and rescues bone morphogenetic protein 2-induced osteoblastogenic differentiation

S. Wang; W. Bi; Y. Liu; J. Cheng; W. Sun; G. Wu; X. Xu

doi:10.2147/DDDT.S215786

The antagonist of retinoic acid receptor α, ER-50891 antagonizes the inhibitive effect of all-trans retinoic acid and rescues bone morphogenetic protein 2-induced osteoblastogenic differentiation

S. Wang, W. Bi, Y. Liu, J. Cheng, W. Sun, G. Wu, X. Xu

Reconstructive Oral Care

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Hypervitaminosis A, alcoholism or medical treatment for acute promyelocytic leukaemia may cause unphysiologically high accumulation of all-trans retinoic acid (ATRA), which could inhibit osteoblastogenesis, thereby triggering osteoporosis. We have shown that bone morphogenetic protein-2 (BMP-2) can only partially antagonize the inhibitive effects of ATRA. In this study, we hypothesized that antagonists of retinoic acid receptors (RARs) could further antagonize the inhibitive effect of ATRA and rescue BMP2-induced osteoblastogenesis. Materials and Methods: We first screened the dose-dependent effects of the specific antagonists of RAR α, β and γ and transforming growth factor-beta receptor (ER-50891, LE-135, MM11253, and SB-43142, respectively) on ATRA-induced inhibition of the total cell metabolic activity and proliferation of preosteoblasts. We selected ER-50891 and tested its effects on osteoblastogenesis with the presence or absence of 1 μM ATRA and/or 200 ng/mL BMP-2. We measured the following parameters: Alkaline phosphatase activity (ALP), osteocalcin (OCN) expression and extracellular matrix mineralization as well as the level of phosphorylated Smad1/5. Results: ER-50891 but not LE-135, MM11253, or SB-431542 significantly antagonized the inhibition of ATRA and enhanced the total cell metabolic activity and proliferation of preosteoblasts. Dose-dependent assays show ER-50891 could also rescue ATRA inhibited OCN expression and mineralization with or without the induction of BMP. ER-50891 also suppressed the ALP activity that was synergistically enhanced by BMP and ATRA. Neither ATRA, nor ER-50891 or their combination significantly affected the level of BMP-induced phosphorylated Smad1/5. Conclusion: The antagonist of RARα, ER-50891 could significantly attenuate ATRA’s inhibitive effects on BMP 2-induced osteoblastogenesis.

Original language	English
Pages (from-to)	297-308
Number of pages	12
Journal	Drug Design, Development and Therapy
Volume	14
DOIs	https://doi.org/10.2147/DDDT.S215786
Publication status	Published - 1 Jan 2020

Funding

This study was supported by the funds of National Natural Science Foundation of China (81470724 and 81600844), Hebei Provincial Natural Science Foundation of China (H2017209238), Hebei Provincial Health Planning Commission Project Foundation of China (20180738 and 20191103), Zhejiang Provincial Natural Science Foundation of China (LY17H140010 and LQ18H140003), Zhejiang Provincial Department of Education (Y201636248), Science and Technology Department of Zhejiang Province (2017C33168).

Funders	Funder number
Hebei Provincial Health Planning Commission Project Foundation of China	20191103, 20180738
Hebei Provincial Natural Science Foundation of China
Zhejiang Provincial Department of Education
Zhejiang Provincial Natural Science Foundation of China
National Natural Science Foundation of China	81600844, 81470724
Natural Science Foundation of Hebei Province	H2017209238
Natural Science Foundation of Zhejiang Province	LQ18H140003, LY17H140010
Department of Education of Zhejiang Province	Y201636248
Science and Technology Department of Zhejiang Province	2017C33168

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10.2147/DDDT.S215786

https://hdl.handle.net/11245.1/250821ea-e9df-4072-aac2-46d2ad73a624

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@article{7e1024706f9846cd9cc53568f0bee16f,

title = "The antagonist of retinoic acid receptor α, ER-50891 antagonizes the inhibitive effect of all-trans retinoic acid and rescues bone morphogenetic protein 2-induced osteoblastogenic differentiation",

abstract = "Background: Hypervitaminosis A, alcoholism or medical treatment for acute promyelocytic leukaemia may cause unphysiologically high accumulation of all-trans retinoic acid (ATRA), which could inhibit osteoblastogenesis, thereby triggering osteoporosis. We have shown that bone morphogenetic protein-2 (BMP-2) can only partially antagonize the inhibitive effects of ATRA. In this study, we hypothesized that antagonists of retinoic acid receptors (RARs) could further antagonize the inhibitive effect of ATRA and rescue BMP2-induced osteoblastogenesis. Materials and Methods: We first screened the dose-dependent effects of the specific antagonists of RAR α, β and γ and transforming growth factor-beta receptor (ER-50891, LE-135, MM11253, and SB-43142, respectively) on ATRA-induced inhibition of the total cell metabolic activity and proliferation of preosteoblasts. We selected ER-50891 and tested its effects on osteoblastogenesis with the presence or absence of 1 μM ATRA and/or 200 ng/mL BMP-2. We measured the following parameters: Alkaline phosphatase activity (ALP), osteocalcin (OCN) expression and extracellular matrix mineralization as well as the level of phosphorylated Smad1/5. Results: ER-50891 but not LE-135, MM11253, or SB-431542 significantly antagonized the inhibition of ATRA and enhanced the total cell metabolic activity and proliferation of preosteoblasts. Dose-dependent assays show ER-50891 could also rescue ATRA inhibited OCN expression and mineralization with or without the induction of BMP. ER-50891 also suppressed the ALP activity that was synergistically enhanced by BMP and ATRA. Neither ATRA, nor ER-50891 or their combination significantly affected the level of BMP-induced phosphorylated Smad1/5. Conclusion: The antagonist of RARα, ER-50891 could significantly attenuate ATRA{\textquoteright}s inhibitive effects on BMP 2-induced osteoblastogenesis.",

author = "S. Wang and W. Bi and Y. Liu and J. Cheng and W. Sun and G. Wu and X. Xu",

year = "2020",

month = jan,

day = "1",

doi = "10.2147/DDDT.S215786",

language = "English",

volume = "14",

pages = "297--308",

journal = "Drug Design, Development and Therapy",

issn = "1177-8881",

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The antagonist of retinoic acid receptor α, ER-50891 antagonizes the inhibitive effect of all-trans retinoic acid and rescues bone morphogenetic protein 2-induced osteoblastogenic differentiation. / Wang, S.; Bi, W.; Liu, Y. et al.
In: Drug Design, Development and Therapy, Vol. 14, 01.01.2020, p. 297-308.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - The antagonist of retinoic acid receptor α, ER-50891 antagonizes the inhibitive effect of all-trans retinoic acid and rescues bone morphogenetic protein 2-induced osteoblastogenic differentiation

AU - Wang, S.

AU - Bi, W.

AU - Liu, Y.

AU - Cheng, J.

AU - Sun, W.

AU - Wu, G.

AU - Xu, X.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Background: Hypervitaminosis A, alcoholism or medical treatment for acute promyelocytic leukaemia may cause unphysiologically high accumulation of all-trans retinoic acid (ATRA), which could inhibit osteoblastogenesis, thereby triggering osteoporosis. We have shown that bone morphogenetic protein-2 (BMP-2) can only partially antagonize the inhibitive effects of ATRA. In this study, we hypothesized that antagonists of retinoic acid receptors (RARs) could further antagonize the inhibitive effect of ATRA and rescue BMP2-induced osteoblastogenesis. Materials and Methods: We first screened the dose-dependent effects of the specific antagonists of RAR α, β and γ and transforming growth factor-beta receptor (ER-50891, LE-135, MM11253, and SB-43142, respectively) on ATRA-induced inhibition of the total cell metabolic activity and proliferation of preosteoblasts. We selected ER-50891 and tested its effects on osteoblastogenesis with the presence or absence of 1 μM ATRA and/or 200 ng/mL BMP-2. We measured the following parameters: Alkaline phosphatase activity (ALP), osteocalcin (OCN) expression and extracellular matrix mineralization as well as the level of phosphorylated Smad1/5. Results: ER-50891 but not LE-135, MM11253, or SB-431542 significantly antagonized the inhibition of ATRA and enhanced the total cell metabolic activity and proliferation of preosteoblasts. Dose-dependent assays show ER-50891 could also rescue ATRA inhibited OCN expression and mineralization with or without the induction of BMP. ER-50891 also suppressed the ALP activity that was synergistically enhanced by BMP and ATRA. Neither ATRA, nor ER-50891 or their combination significantly affected the level of BMP-induced phosphorylated Smad1/5. Conclusion: The antagonist of RARα, ER-50891 could significantly attenuate ATRA’s inhibitive effects on BMP 2-induced osteoblastogenesis.

AB - Background: Hypervitaminosis A, alcoholism or medical treatment for acute promyelocytic leukaemia may cause unphysiologically high accumulation of all-trans retinoic acid (ATRA), which could inhibit osteoblastogenesis, thereby triggering osteoporosis. We have shown that bone morphogenetic protein-2 (BMP-2) can only partially antagonize the inhibitive effects of ATRA. In this study, we hypothesized that antagonists of retinoic acid receptors (RARs) could further antagonize the inhibitive effect of ATRA and rescue BMP2-induced osteoblastogenesis. Materials and Methods: We first screened the dose-dependent effects of the specific antagonists of RAR α, β and γ and transforming growth factor-beta receptor (ER-50891, LE-135, MM11253, and SB-43142, respectively) on ATRA-induced inhibition of the total cell metabolic activity and proliferation of preosteoblasts. We selected ER-50891 and tested its effects on osteoblastogenesis with the presence or absence of 1 μM ATRA and/or 200 ng/mL BMP-2. We measured the following parameters: Alkaline phosphatase activity (ALP), osteocalcin (OCN) expression and extracellular matrix mineralization as well as the level of phosphorylated Smad1/5. Results: ER-50891 but not LE-135, MM11253, or SB-431542 significantly antagonized the inhibition of ATRA and enhanced the total cell metabolic activity and proliferation of preosteoblasts. Dose-dependent assays show ER-50891 could also rescue ATRA inhibited OCN expression and mineralization with or without the induction of BMP. ER-50891 also suppressed the ALP activity that was synergistically enhanced by BMP and ATRA. Neither ATRA, nor ER-50891 or their combination significantly affected the level of BMP-induced phosphorylated Smad1/5. Conclusion: The antagonist of RARα, ER-50891 could significantly attenuate ATRA’s inhibitive effects on BMP 2-induced osteoblastogenesis.

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U2 - 10.2147/DDDT.S215786

DO - 10.2147/DDDT.S215786

M3 - Article

C2 - 32158187

SN - 1177-8881

VL - 14

SP - 297

EP - 308

JO - Drug Design, Development and Therapy

JF - Drug Design, Development and Therapy

ER -

The antagonist of retinoic acid receptor α, ER-50891 antagonizes the inhibitive effect of all-trans retinoic acid and rescues bone morphogenetic protein 2-induced osteoblastogenic differentiation

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