Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

Green, Alanna C.; Kocovski, Pece; Jovic, Tanja; Walia, Mannu; Chandraratna, Rosh; Martin, T. J.; Baker, Emma K.; Purton, Louise E.

doi:10.1016/j.yexcr.2016.12.007

Cited by 44 publications

(37 citation statements)

References 55 publications

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“…SFRP4 directly inhibits the excessive keratinocyte proliferation evoked, and decreases the severity of the psoriasiform skin phenotype, including decreased acanthosis and reduced leukocyte infiltration [17]. Recently, Green et al indicated that SFRP4 could be a direct target gene of RARs, and RAR agonist induced the significant upregulation of SFRP4 [28]. Furthermore, acitretin is a member of the RAR agonist family, so we speculated that acitretin may alter the transcriptional regulation of SFRP4 , such as encoding soluble Wnt antagonists and also ligands and receptors of the Notch pathway [25,29].…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing in Psoriasis Patients Contributes to Studies of Acitretin Treatment Difference

Zhou

Kuang

et al. 2017

IJMS

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Psoriasis vulgaris is an immune-mediated inflammatory skin disease. Although acitretin is a widely used synthetic retinoid for moderate to severe psoriasis, little is known about patients’ genetics in response to this drug. In this study, 179 patients were enrolled in either the discovery set (13 patients) or replication set (166 patients). The discovery set was sequenced by whole exome sequencing and sequential validation was conducted in the replication set by MassArray assays. Four SNPs (single nucleotide polymorphisms) (rs1105223T>C in CRB2, rs11086065A>G in ANKLE1, rs3821414T>C in ARHGEF3, rs1802073 T>G in SFRP4) were found to be significantly associated with acitretin response in either co-dominant or dominant models via multivariable logistic regression analysis, while CRB2 rs1105223CC (OR = 4.10, 95% CI = 1.46–11.5, p = 0.007) and ANKLE1 rs11086065AG/GG (OR = 2.76, 95% CI = 1.42–5.37, p = 0.003) were associated with no response to acitretin after 8-week treatment. Meanwhile, ARHGEF3 rs3821414CT/CC (OR = 0.25, 95% CI = 0.10–0.68, p = 0.006) and SFRP4 rs1802073GG/GT (OR = 2.40, 95% CI, 1.23–4.70, p = 0.011) were associated with a higher response rate. Four new genetic variations with potential influences on the response to acitretin were found in this study which may serve as genetic markers for acitretin in psoriasis patients.

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Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing in Psoriasis Patients Contributes to Studies of Acitretin Treatment Difference

Zhou

Kuang

et al. 2017

IJMS

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“…The upregulation of expression of the TGFβ/SMAD pathway and Wnt/β-catenin pathway by RAR agonists may potentially block the function of C/EBPβ and PPARγ. We found that the main RAR subtype mediating this effect is RARβ, although some reports have shown that RAR agonist regulates adipogenesis through RARγ and RARα in some cell systems [8,25]. In contrast, RXR agonists significantly promoted adipogenesis in hBMSCs, but inhibited it in SW872 cells, displaying cell type-specific differences.…”

Section: Discussionmentioning

confidence: 70%

“…RARs are negative regulators of osteoblast and adipocyte differentiation [8]. Retinoic acid (RA) inhibits growth at a high concentration (100 μM) and inhibits differentiation at a low concentration (0.1–10 μM) in preadipocytes [9].…”

Section: Introductionmentioning

confidence: 99%

Retinoids Regulate Adipogenesis Involving the TGFβ/SMAD and Wnt/β-Catenin Pathways in Human Bone Marrow Mesenchymal Stem Cells

Cao

Yao

et al. 2017

IJMS

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Retinoids may regulate cell differentiation as ligands of retinoic acid receptors (RARs) and/or retinoid X receptors (RXRs). We showed that RAR agonists promoted adipogenesis by upregulating the expression of CCAAT/enhancer-binding protein β (C/EBPβ) in the early stages, but blocked adipogenesis at a later stage in human bone marrow mesenchymal stem cells (hBMSCs). RXR agonists promoted adipogenesis at all time points in hBMSCs. The effect of RAR agonists was mediated mainly by the RARβ subtype. RAR agonists, in contrast to RXR agonists, significantly promoted the expression of RARβ. Knockdown of the RARβ gene via small hairpin RNA (shRNA) attenuated the inhibition of RAR agonists toward adipogenesis. Furthermore, we found that RAR agonists upregulated the transforming growth factor β (TGFβ)/SMAD pathway and Wnt/β-catenin pathway on adipogenesis in hBMSCs, and the stimulating effects were noticeably decreased with the RARβ gene knockdown. Both RAR agonists and RXR agonists inhibited adipogenesis and blocked the promoter activity of C/EBPβ and peroxisome proliferator-activated receptor γ (PPARγ) in SW872 cell. These results indicated the RAR agonists perform dual roles in adipogenesis in hBMSCs, and the TGFβ/SMAD pathway and Wnt/β-catenin pathway may involve the inhibitory effect of RAR agonists. RARβ is the main receptor subtype mediating the effect. The roles of RXR agonists in adipogenesis exhibited cell type-specific differences, and may be based on the integration of signals from different RXR dimers.

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“…An intimate correlation exists between microbiota and systemic metabolism [42]; therefore, we chose the metabolic-and developmental-relevant genes for further study by GO annotation analysis. Of the altered genes seen and combined with prior literature, the most likely candidate is the RA signaling pathway [43][44][45]. RA is a vitamin-A-derived, nonpeptidic, structurally simple lipophilic molecule, which plays a pleiotropic role during development.…”

Section: Discussionmentioning

confidence: 99%

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression

You

Zhu

et al. 2020

IJMS

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Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor α (RARα) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-κB signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role.

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Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

Cited by 44 publications

References 55 publications

Whole Exome Sequencing in Psoriasis Patients Contributes to Studies of Acitretin Treatment Difference

Whole Exome Sequencing in Psoriasis Patients Contributes to Studies of Acitretin Treatment Difference

Retinoids Regulate Adipogenesis Involving the TGFβ/SMAD and Wnt/β-Catenin Pathways in Human Bone Marrow Mesenchymal Stem Cells

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression

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