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Mangiferin reduces the inhibition of chondrogenic differentiation by IL-1β in mesenchymal stem cells from subchondral bone and targets multiple aspects of the Smad and SOX9 pathways.

Huh JE, Koh PS, Seo BK, Park YC, Baek YH, Lee JD, Park DS - Int J Mol Sci (2014)

Bottom Line: Mangiferin is a natural immunomodulator found in plants including mango trees.In IL-1β-stimulated MSCs, mangiferin significantly reversed the production of TGF-β, BMP-2, BMP-4, SOX9, Col2α1, cartilage link protein, and aggrecan, as well as matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS5).In conclusion, mangiferin exhibits both chondrogenic and chondroprotective effects on damaged MSCs and mediates these effects by targeting multiple aspects of the Smad and SOX9 signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: East-West Bone & Joint Research Institute, Kyung Hee University, 149, Sangil-dong, Gangdong-gu, Seoul 134-727, Korea. jehuh2551@hanmail.net.

ABSTRACT
Mangiferin is a natural immunomodulator found in plants including mango trees. The effects of mangiferin on chondrogenesis and cartilage repair have not yet been reported. This study was designed to determine the effect of mangiferin on chondrogenic differentiation in IL-1β-stimulated mesenchymal stem cells (MSCs) from subchondral bone and to explore the mechanisms underlying these effects. MSCs were isolated from the subchondral bone of rabbit and treated with mangiferin alone and/or interleukin-1β (IL-1β). Mangiferin induced chondrogenic differentiation in MSCs by upregulating transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, and BMP-4 and several key markers of chondrogenesis, including sex-determining region Y-box (SRY-box) containing gene 9 (SOX9), type 2α1 collagen (Col2α1), cartilage link protein, and aggrecan. In IL-1β-stimulated MSCs, mangiferin significantly reversed the production of TGF-β, BMP-2, BMP-4, SOX9, Col2α1, cartilage link protein, and aggrecan, as well as matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS5). Mangiferin upregulated the phosphorylation of Smad 2, Smad 3, Smad 1/5/8, and SOX9 in IL-1β-stimulated MSCs. In the presence of mangiferin, SOX9 siRNA suppressed the activation of Smad 2, Smad 3, Smad 1/5/8, aggrecan, and Col2α1 expression. In conclusion, mangiferin exhibits both chondrogenic and chondroprotective effects on damaged MSCs and mediates these effects by targeting multiple aspects of the Smad and SOX9 signaling pathways.

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Schematic model of the pathways by which mangiferin stimulates SOX-9, a key transcription factor of TGF-β/BMPs-induced chondrogenesis, and activates the phosphorylation of Smad 1/5/8 and Smad 2/3 signaling pathways. → activation; ┤ inhibition; ↑ increase; ↓ decrease.
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ijms-15-16025-f006: Schematic model of the pathways by which mangiferin stimulates SOX-9, a key transcription factor of TGF-β/BMPs-induced chondrogenesis, and activates the phosphorylation of Smad 1/5/8 and Smad 2/3 signaling pathways. → activation; ┤ inhibition; ↑ increase; ↓ decrease.

Mentions: We observed that mangiferin induces chondrogenic differentiation in subchondral MSCs by enhancing the expression of chondrogenic markers (Col2α1, SOX9, cartilage link protein, and aggrecan) and TGF-β/BMPs. We also observed that mangiferin has chondroprotective effects, by stimulating the induction of anabolic genes (BMP-2, BMP-4, and TGF-β) and inhibiting the expression of catabolic genes (MMP-1, MMP-13, and ADAMS-5), in IL-1β-stimulated MSCs, and that these effects are mediated through the phosphorylation of the Smad 2, Smad 3, Smad 1/5/8, and SOX9 signaling pathways (Figure 6).


Mangiferin reduces the inhibition of chondrogenic differentiation by IL-1β in mesenchymal stem cells from subchondral bone and targets multiple aspects of the Smad and SOX9 pathways.

Huh JE, Koh PS, Seo BK, Park YC, Baek YH, Lee JD, Park DS - Int J Mol Sci (2014)

Schematic model of the pathways by which mangiferin stimulates SOX-9, a key transcription factor of TGF-β/BMPs-induced chondrogenesis, and activates the phosphorylation of Smad 1/5/8 and Smad 2/3 signaling pathways. → activation; ┤ inhibition; ↑ increase; ↓ decrease.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4200868&req=5

ijms-15-16025-f006: Schematic model of the pathways by which mangiferin stimulates SOX-9, a key transcription factor of TGF-β/BMPs-induced chondrogenesis, and activates the phosphorylation of Smad 1/5/8 and Smad 2/3 signaling pathways. → activation; ┤ inhibition; ↑ increase; ↓ decrease.
Mentions: We observed that mangiferin induces chondrogenic differentiation in subchondral MSCs by enhancing the expression of chondrogenic markers (Col2α1, SOX9, cartilage link protein, and aggrecan) and TGF-β/BMPs. We also observed that mangiferin has chondroprotective effects, by stimulating the induction of anabolic genes (BMP-2, BMP-4, and TGF-β) and inhibiting the expression of catabolic genes (MMP-1, MMP-13, and ADAMS-5), in IL-1β-stimulated MSCs, and that these effects are mediated through the phosphorylation of the Smad 2, Smad 3, Smad 1/5/8, and SOX9 signaling pathways (Figure 6).

Bottom Line: Mangiferin is a natural immunomodulator found in plants including mango trees.In IL-1β-stimulated MSCs, mangiferin significantly reversed the production of TGF-β, BMP-2, BMP-4, SOX9, Col2α1, cartilage link protein, and aggrecan, as well as matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS5).In conclusion, mangiferin exhibits both chondrogenic and chondroprotective effects on damaged MSCs and mediates these effects by targeting multiple aspects of the Smad and SOX9 signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: East-West Bone & Joint Research Institute, Kyung Hee University, 149, Sangil-dong, Gangdong-gu, Seoul 134-727, Korea. jehuh2551@hanmail.net.

ABSTRACT
Mangiferin is a natural immunomodulator found in plants including mango trees. The effects of mangiferin on chondrogenesis and cartilage repair have not yet been reported. This study was designed to determine the effect of mangiferin on chondrogenic differentiation in IL-1β-stimulated mesenchymal stem cells (MSCs) from subchondral bone and to explore the mechanisms underlying these effects. MSCs were isolated from the subchondral bone of rabbit and treated with mangiferin alone and/or interleukin-1β (IL-1β). Mangiferin induced chondrogenic differentiation in MSCs by upregulating transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, and BMP-4 and several key markers of chondrogenesis, including sex-determining region Y-box (SRY-box) containing gene 9 (SOX9), type 2α1 collagen (Col2α1), cartilage link protein, and aggrecan. In IL-1β-stimulated MSCs, mangiferin significantly reversed the production of TGF-β, BMP-2, BMP-4, SOX9, Col2α1, cartilage link protein, and aggrecan, as well as matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS5). Mangiferin upregulated the phosphorylation of Smad 2, Smad 3, Smad 1/5/8, and SOX9 in IL-1β-stimulated MSCs. In the presence of mangiferin, SOX9 siRNA suppressed the activation of Smad 2, Smad 3, Smad 1/5/8, aggrecan, and Col2α1 expression. In conclusion, mangiferin exhibits both chondrogenic and chondroprotective effects on damaged MSCs and mediates these effects by targeting multiple aspects of the Smad and SOX9 signaling pathways.

Show MeSH
Related in: MedlinePlus