Fluocinolone acetonide is a potent synergistic factor of TGF-β3-associated chondrogenesis of bone marrow-derived mesenchymal stem cells for articular surface regeneration

Emilio satoshi Hara, Mitsuaki Ono, Hai Thanh Pham, Wataru Sonoyama, Satoshi Kubota, Masaharu Takigawa, Takuya Matsumoto, Marian F. Young, Bjorn R. Olsen, Takuo Kuboki

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Abstract

Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells.

Original languageEnglish
Pages (from-to)1585-1596
Number of pages12
JournalJournal of Bone and Mineral Research
Volume30
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

Fingerprint

Fluocinolone Acetonide
Chondrogenesis
Mesenchymal Stromal Cells
Transforming Growth Factor beta
Regeneration
Joints
Bone Marrow
Glucocorticoid Receptors
Triamcinolone Acetonide
Articular Cartilage
Dexamethasone
Mifepristone
Sirolimus
Knee Joint

Keywords

  • BMP
  • cartilage regeneration
  • chondrogenesis
  • fluocinolone acetonide
  • glucocorticoids
  • stem cells
  • TGF-β

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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title = "Fluocinolone acetonide is a potent synergistic factor of TGF-β3-associated chondrogenesis of bone marrow-derived mesenchymal stem cells for articular surface regeneration",
abstract = "Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells.",
keywords = "BMP, cartilage regeneration, chondrogenesis, fluocinolone acetonide, glucocorticoids, stem cells, TGF-β",
author = "Emilio satoshi Hara and Mitsuaki Ono and Pham, {Hai Thanh} and Wataru Sonoyama and Satoshi Kubota and Masaharu Takigawa and Takuya Matsumoto and Young, {Marian F.} and Olsen, {Bjorn R.} and Takuo Kuboki",
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T1 - Fluocinolone acetonide is a potent synergistic factor of TGF-β3-associated chondrogenesis of bone marrow-derived mesenchymal stem cells for articular surface regeneration

AU - Hara, Emilio satoshi

AU - Ono, Mitsuaki

AU - Pham, Hai Thanh

AU - Sonoyama, Wataru

AU - Kubota, Satoshi

AU - Takigawa, Masaharu

AU - Matsumoto, Takuya

AU - Young, Marian F.

AU - Olsen, Bjorn R.

AU - Kuboki, Takuo

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells.

AB - Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells.

KW - BMP

KW - cartilage regeneration

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