Smad3 Induces Chondrogenesis through the Activation of SOX9 via CREB-binding Protein/p300 Recruitment

Furumatsu, Takayuki; Tsuda, Masanao; Taniguchi, Noboru; Tajima, Yoshitaka; Asahara, Hiroshi

doi:10.1074/jbc.m413913200

Cited by 284 publications

(292 citation statements)

References 66 publications

(67 reference statements)

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“…In chondrogenesis, TGF-β stimulation is necessary for chondrogenic differentiation derived from MSCs [10]. We have previously described that TGF-β signal Smad3 promotes the early chondrogenesis through the activation of Sox9 [17]. TGF-β-regulated Smad3 also activates the Sox9-dependent transcription on chromatin without influencing Sox9 expression itself [32].…”

Section: Discussionmentioning

confidence: 99%

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Anterior cruciate ligament-derived cells have high chondrogenic potential

Furumatsu

Hachioji

Saiga

et al. 2010

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 99%

“…Ligament-derived cells between passage 3 and 6 were used. (CIM) supplemented with 10 ng/ml of BMP-2 and/or recombinant human TGF-β3 (R&D Systems) as described [17]. Pellets were observed with hematoxylin-eosin (HE) and safranin O staining [18].…”

Section: Methodsmentioning

confidence: 99%

Anterior cruciate ligament-derived cells have high chondrogenic potential

Furumatsu

Hachioji

Saiga

et al. 2010

Biochemical and Biophysical Research Communications

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“…On the basis of these preliminary experiments, we chose to prime NCSCs by addition of 1 ng/ml TGFb1 for 4 hours and to examine the expression of the NCSC markers p75 neurotrophin receptor (p75 NTR ) and Sox10 transcription factor [16,17] and of the bonafide marker of early osteochondrocytic lineage, Sox9 transcription factor [18,19]. As previously reported for MSCs [20], Sox9 expression was induced by TGFb1 in NCSCs after this priming period (Fig. 1C, 1D and see Table 1 for quantitative analysis).…”

Section: Generation Of Mesenchymal Progenitors From Ncsc Cultures By mentioning

confidence: 99%

Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells

et al. 2011

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During vertebrate development, neural crest stem cells (NCSCs) give rise to neural cells of the peripheral nervous system and to a variety of mesenchymal cell types, including smooth muscle, craniofacial chondrocytes, and osteocytes. Consistently, mesenchymal stem cells (MSCs) have recently been shown to derive in part from the neural crest (NC), although the mechanisms underlying MSC generation remains to be identified. Here, we show that transforming growth factor b (TGFb)-mediated suppression of the NCSC transcription factor Sox10 induces a switch in neural to mesenchymal potential in NCSCs. In vitro and in vivo, TGFb signal inactivation results in persistent Sox10 expression, decreased cell cycle exit, and perturbed generation of mesenchymal derivatives, which eventually leads to defective morphogenesis. In contrast, TGFb-mediated downregulation of Sox10 or its genetic inactivation suppresses neural potential, confers mesenchymal potential to NC cells in vitro, and promotes cell cycle exit and precocious mesenchymal differentiation in vivo. Thus, negative regulation of Sox10 by TGFb signaling promotes the generation of mesenchymal progenitors from NCSCs. Our study might lay the grounds for future applications demanding defined populations of MSCs for regenerative medicine. STEM CELLS 2011;29:689-699 Disclosure of potential conflicts of interest is found at the end of this article.

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“…In current study, we found that Midazolam inhibits protein levels of SOX9 but not SOX5 and SOX6 in chondrogenic induction. One possible reason is that SOX9 is found to be one of the TGF‐β/Smad3 downstream effectors46 to regulate chondrogenesis. The down‐regulation of SOX9 may result in disruption of the formation of SOX trio, which in turn inhibits the transcription of chondrogenesis‐related genes.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated Smads can interact with Smad4 to become a complex, and this complex translocates into the nucleus and turns on gene transcription 55. Smad3 is able to activate SOX9 via recruitment of CREB‐binding protein/p300 46. In addition, TGF‐β/Smad signalling is essential for osteocartilage development, bone homeostasis and MSC fate decision 57.…”

Section: Discussionmentioning

confidence: 99%

Midazolam inhibits chondrogenesis via peripheral benzodiazepine receptor in human mesenchymal stem cells

Chen

Huang

et al. 2018

J Cellular Molecular Medi

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Midazolam, a benzodiazepine derivative, is widely used for sedation and surgery. However, previous studies have demonstrated that Midazolam is associated with increased risks of congenital malformations, such as dwarfism, when used during early pregnancy. Recent studies have also demonstrated that Midazolam suppresses osteogenesis of mesenchymal stem cells (MSCs). Given that hypertrophic chondrocytes can differentiate into osteoblast and osteocytes and contribute to endochondral bone formation, the effect of Midazolam on chondrogenesis remains unclear. In this study, we applied a human MSC line, the KP cell, to serve as an in vitro model to study the effect of Midazolam on chondrogenesis. We first successfully established an in vitro chondrogenic model in a micromass culture or a 2D high‐density culture performed with TGF‐β‐driven chondrogenic induction medium. Treatment of the Midazolam dose‐dependently inhibited chondrogenesis, examined using Alcian blue‐stained glycosaminoglycans and the expression of chondrogenic markers, such as SOX9 and type II collagen. Inhibition of Midazolam by peripheral benzodiazepine receptor (PBR) antagonist PK11195 or small interfering RNA rescued the inhibitory effects of Midazolam on chondrogenesis. In addition, Midazolam suppressed transforming growth factor‐β‐induced Smad3 phosphorylation, and this inhibitory effect could be rescued using PBR antagonist PK11195. This study provides a possible explanation for Midazolam‐induced congenital malformations of the musculoskeletal system through PBR.

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Smad3 Induces Chondrogenesis through the Activation of SOX9 via CREB-binding Protein/p300 Recruitment

Cited by 284 publications

References 66 publications

Anterior cruciate ligament-derived cells have high chondrogenic potential

Anterior cruciate ligament-derived cells have high chondrogenic potential

Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells

Midazolam inhibits chondrogenesis via peripheral benzodiazepine receptor in human mesenchymal stem cells

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