All-trans retinoic acid shifts rosiglitazone-induced adipogenic differentiation to osteogenic differentiation in mouse embryonic fibroblasts

Abstract

Rosiglitazone (RSG) is a potent drug used in the treatment of insulin resistance; however, it is associated with marked skeletal toxicity. RSG-induced osteoporosis may contribute to the promotion of adipogenic differentiation at the expense of osteogenic differentiation in bone marrow stromal cells. The aim of this study was to investigate whether RSG-induced bone toxicity can be reversed by combined treatment with all-trans retinoic acid (ATRA). We examined different osteogenic markers in mouse embryonic fibroblasts (MEFs) following treatment with RSG, ATRA, or RSG and ATRA in combination. We examined the effects of RSG and/or ATRA on ectopic bone formation, and dissected the possible molecular mechanisms underlying this process. We found that ATRA or RSG both induced alkaline phosphatase (ALP) activity in the MEFs, and that the ATRA-induced ALP activity was enhanced by RSG and vice versa. However, only the combination of RSG and ATRA increased the expression of osteopontin and osteocalcin, promoted matrix mineralization, and induced ectopic ossification in MEFs. Mechanistically, we found that the osteogenic differentiation induced by the combination of RSG and ATRA may be mediated partly by suppressing RSG-induced adipogenic differentiation and activating bone morphogenetic protein (BMP)/Smad signaling. On the whole, our findings demonstrate that RSG in combination with ATRA promotes the commitment of MEFs to the osteoblast lineage. Thus, the combination of these two agents may prove to be a promising and novel therapeutic regimen for insulin resistance without skeletal toxicity. It may also be a better strategy with which to prevent RSG-induced osteoporosis.

RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia

“…By contrast, RSPO2 decreased BMP signaling activity induced by BMP4 or siRSPO2 (Figures S1I-S1K). In addition, we stimulated THP-1 cells with all-trans-retinoic acid (ATRA), which regulates BMP signaling in multiple contexts (Cruz et al, 2019;Shao et al, 2016). ATRA administration induced Smad1-phosphorylation and…”

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

“…Correspondingly, retinoic acid has been shown to induce the osteogenic differentiation of stromal cells from both visceral and subcutaneous adipose tissue depots (178). Moreover, as previously demonstrated, in mouse embryonic fibroblasts, 0.4 µM ATRA promotes a shift to osteogenesis from rosiglitazone-induced adipogenic differentiation through the upregulation of Smad1/5/8 phosphorylation and Smad6 expression, resulting in the activation of BMP/Smad pathway (179). At the same time, it has also been observed that pharmacological concentrations of 1-10 µM ATRA inhibit osteoblast proliferation, while increasing its differentiation (180).…”

HIF1α Promotes BMP9‐Mediated Osteoblastic Differentiation and Vascularization by Interacting with CBFA1

“…Nano-Glo Dual-Luciferase Reporter Assay. The iMEFs were seeded in Corning 24-well cell culture plates and transfected with 1 μg firefly luciferase vector, 1 μg Renilla luciferase vector, and 0.5 μg BMP9 binding element luciferase reporter (p12Xsbe-Luc) or Runx2 reporter plasmid (p6Xose2-Luc) per flask using Lipofectamine 2000 [22,23]. Twenty-four hours after transfection, the cells were reseeded in 24-well plates and treated with DMSO, HIF1α, and/or Runx2.…”