<p>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</p>

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.

Role of vitamins beyond vitamin D3 in bone health and osteoporosis (Review)

“…The inhibitory effect of 1 μ M ATRA on BMP-2-induced osteoblastogenesis has also been shown to be dependent on RARα signaling ( 191 ). These findings corroborate those of an earlier study by Nuka et al ( 192 ), establishing a key role for RARα and RARβ signaling activation in the inhibition of SV HFO osteoblast cell line mineralization in response to 0.1 μ M ATRA treatment.…”

Rapid human‐derived iPSC osteogenesis combined with three‐dimensionally printed Ti6Al4V scaffolds for the repair of bone defects

“…Retinoic acid (RA) was used to accelerate the osteogenic induction (OI) of iPSCs. RA is a metabolite of vitamin A1 that plays critical roles in growth and development, such as osteochondral development and osteoblastogenesis (Scholtes et al, 2018; S. Wang et al, 2020). Here, different concentrations of RA were used to osteo‐induce the iPSCs.…”