All-trans retinoic acid inhibited chondrogenesis of mouse embryonic palate mesenchymal cells by down-regulation of TGF-β/Smad signaling

Yu, Zengli; Xing, Ying

doi:10.1016/j.bbrc.2005.12.100

Cited by 46 publications

(44 citation statements)

References 32 publications

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“…In some cell lines, RA increases production of Tgf␤1 and its receptors, leading to growth inhibition (Batova et al, 1992;Danielpour, 1996;Falk et al, 1991;Glick et al, 1989;Imai et al, 1997;Kojima and Rifkin, 1993). RA, however, has also been reported to inhibit endogenous Tgf␤ signaling in the mesenchyme of the developing inner ear (Frenz and Liu, 2000) and palate (Yu and Xing, 2006) in mice. Disruption of Rxra in mice results in abnormal upregulation of Tgfb2 in cardiac tissue (Kubalak et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Tgfβ signaling by endogenous retinoic acid is essential for primary lung bud induction

et al. 2007

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Disruption of retinoic acid (RA) signaling during early development results in severe respiratory tract abnormalities, including lung agenesis. Previous studies suggest that this might result from failure to selectively induce fibroblast growth factor 10 (Fgf10) in the prospective lung region of the foregut. Little is known about the RA-dependent pathways present in the foregut that may be crucial for lung formation. By performing global gene expression analysis of RA-deficient foreguts from a genetic [retinaldehyde dehydrogenase 2 (Raldh2)-null] and a pharmacological (BMS493-treated)mouse model, we found upregulation of a large number of Tgfβ targets. Increased Smad2 phosphorylation further suggested that Tgfβ signaling was hyperactive in these foreguts when lung agenesis was observed. RA rescue of the lung phenotype was associated with low levels of Smad2 phosphorylation and downregulation of Tgfβ targets in Raldh2-null foreguts. Interestingly, the lung defect that resulted from RA-deficiency could be reproduced in RA-sufficient foreguts by hyperactivating Tgfβ signaling with exogenous TGFβ1. Preventing activation of endogenous Tgfβsignaling with a pan-specific TGFβ-blocking antibody allowed bud formation and gene expression in the lung field of both Raldh2-null and BMS493-treated foreguts. Our data support a novel mechanism of RA-Tgfβ-Fgf10 interactions in the developing foregut, in which endogenous RA controls Tgfβ activity in the prospective lung field to allow local expression of Fgf10 and induction of lung buds.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Tgfβ signaling by endogenous retinoic acid is essential for primary lung bud induction

et al. 2007

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“…MEMP cells were isolated from palate shelves of embryonic day 12 CD1 mouse embryos as described [13]. Briefly, palate shelves were minced and digested with 0.25% trypsin/0.05% EDTA in PBS for 10 min at 37°C with slight shaking.…”

Section: Preparation Of Mepm Micromass Cultures (Mmcs)mentioning

confidence: 99%

“…Indeed, TGF-β activated by RA is thought to mediate the effects of RA on a variety of cell types [11,12]. Our previous study showed that atRA inhibites chondrogenesis by downregulation of TGF-β/Smad signaling in mouse embryonic palate mesenchymal (MEPM) cells grown in micromass cultures [13]. However, the molecular mechanisms of interaction between TGF-β and RA signaling remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Negative Functional Interaction of Retinoic Acid and TGF-β Signaling Mediated by TG-interacting Factor During Chondrogenesis

Zhang

Li²,

Tang³

et al. 2009

Cell Physiol Biochem

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We previously showed that atRA (all-trans Retinoic Acid, atRA) inhibites chondrogenesis by downregulation of TGF-β/Smad signaling. However, the molecular link between RA and TGF-β signaling is unknown. Using a mouse embryo palate mesenchyme micomass cultures (MMCs) system, we explored interactions of RA and TGF-β signaling during chondrogenesis. We found that atRA suppressed chondrogenesis and Smad2/3 phosphorylation regardless of the presence of TGF-β3. Functional assays indicated that TGF-β3 treatment or co-transfection of expressing Smad2/3 vectors suppressed atRA-induced RARE-tk-Luc activity. Conversely, atRA or RAR-overexpression repressed TGF-β3-induced transactivation of the TGF-β-responsive reporter, p3TP-Lux. ChIP assay revealed the binding of the Smad transcriptional co-repressor TGIF (TG-interacting factor, TGIF) to RARβ promoter in control MMCs, but this association was decreased by the addition of RA and increased by TGF-β3, respectively. Further examinations revealed that TGIF exerted a pivotal role in regulating crosstalk of RA and TGF-β signaling, since siRNA knockdown of TGIF partially abolished the ability of atRA to suppress TGF-β3-induced chondrogenesis, whereas forced expression of TGIF blocked the ability of TGF-β3 to relieve atRA-mediated the suppression of chondrogenesis. Furthermore, we demonstrated that the effects of atRA on TGF-β-dependent gene activation and of TGF-β on RA-dependent gene activation are mediated by TGIF with siRNA to downregulate TGIF. Collectively, these findings indicated a negative functional interplay of RA and TGF-β signaling mediated by TGIF to modulate chondrogenesis in MMCs.

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“…However, some investigator found that there was an association between ATRA and TGF-β/Smad signaling pathway. Yu et al 22 found that ATRA treatment significantly increased the level of TGF-β3 in comparison to level in untreated mouse embryonic palate mesenchymal micromass cultures, and ATRA inhibited the phosphorylation of Smad3, and they drew a conclusion that ATRA-induced hypochondrogenesis through regulation of the TGF-β3 pathway. Zhang et al 23 performed a further study in mouse embryonic palate mesenchymal cells (MMCs) and the results were as follows: ATRA inhibited chondrogenesis and the levels of phospho-Smad2/3; whereas, treatment with TGF-β3 strongly induced phospho-Smad2/3 and chondrogenesis.…”

Section: Discussionmentioning

confidence: 99%

All-Trans Retinoic Acid Attenuates the Renal Interstitial Fibrosis Lesion in Rats but Not By Transforming Growth Factor-β1/Smad3 Signaling Pathway

Zhou

Qin

et al. 2012

Renal Failure

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All-trans retinoic acid (ATRA) is an important therapeutic agent for prevention of the renal diseases. Transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway is a key signaling pathway which takes part in the progression of renal interstitial fibrosis (RIF). This investigation was performed to study the effect of ATRA in RIF rats and its effect on the TGF-β1/Smad3 signaling pathway. Sixty Wistar male rats were divided into three groups at random: sham operation group (SHO), model group subjected to unilateral ureteral obstruction (GU), model group treated with ATRA (GA), n ¼ 20, respectively. RIF index, protein expression of TGF-β1, collagen-IV (Col-IV) and fibronectin (FN) in renal interstitium, and mRNA and protein expressions of Smad3 in renal tissue were detected at 14-day and 28-day after surgery. The RIF index was markedly elevated in group GU than in SHO group (p < 0.01), and the RIF index of GA group was alleviated when compared with that in GU group (p < 0.01). Compared with in group SHO, the mRNA/protein expression of Smad3 in renal tissue was significantly increased in group GU (p < 0.01). However, the mRNA and protein expressions of Smad3 in renal tissue in GA group were not markedly alleviated by ATRA treatment when compared with those in GU (each p > 0.05). Protein expressions of TGF-β1, Col-IV, and FN in GU group were markedly increased than those in SHO group (each p < 0.01), and their expressions in GA group were markedly down-regulated by ATRA treatment than those of GU group (all p < 0.01). The protein expression of Smad3 was positively correlated with RIF index, protein expression of TGF-β1, Col-IV or FN (each p < 0.01). In conclusion, ATRA treatment can alleviate the RIF progression in UUO rats. However, ATRA cannot affect the signaling pathway of TGF-β1/Smad3 in the progression of RIF.

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All-trans retinoic acid inhibited chondrogenesis of mouse embryonic palate mesenchymal cells by down-regulation of TGF-β/Smad signaling

Cited by 46 publications

References 32 publications

Inhibition of Tgfβ signaling by endogenous retinoic acid is essential for primary lung bud induction

Inhibition of Tgfβ signaling by endogenous retinoic acid is essential for primary lung bud induction

Negative Functional Interaction of Retinoic Acid and TGF-β Signaling Mediated by TG-interacting Factor During Chondrogenesis

All-Trans Retinoic Acid Attenuates the Renal Interstitial Fibrosis Lesion in Rats but Not By Transforming Growth Factor-β1/Smad3 Signaling Pathway

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