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.
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.|Department of Biomaterials, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Emilio Satoshi
authors.initials: ES
authors.lastname: Hara
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hai Thanh
authors.initials: HT
authors.lastname: Pham
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sonoyama
authors.affiliation: Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takigawa
authors.affiliation: Department of Biomaterials, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institutes of Craniofacial and Dental Research, National Institutes of Health, Bethesda, MD,, USA.
authors.forename: Marian F
authors.initials: MF
authors.lastname: Young
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA,, USA.
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Kuboki
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000737:chemistry; D005260:Female; D005446:Fluocinolone Acetonide / Q000737:chemistry*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D015735:Mifepristone / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D053782:Transforming Growth Factor beta3 / Q000378:metabolism*; D014222:Triamcinolone Acetonide / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D011965:Receptors, Glucocorticoid; C509044:TGFB3 protein, human; C509045:Tgfb3 protein, mouse; D053782:Transforming Growth Factor beta3; D005446:Fluocinolone Acetonide; D015735:Mifepristone; D003907:Dexamethasone; D014222:Triamcinolone Acetonide
keywords: BMP; CARTILAGE REGENERATION; CHONDROGENESIS; FLUOCINOLONE ACETONIDE; GLUCOCORTICOIDS; STEM CELLS; TGF-β