Fluocinolone Acetonide Is a Potent Synergistic Factor of TGF-β3-Associated Chondrogenesis of Bone Marrow-Derived Mesenchymal Stem Cells for Articular Surface Regeneration.
Fluocinolone Acetonide Is a Potent Synergistic Factor of TGF-β3-Associated Chondrogenesis of Bone Marrow-Derived Mesenchymal Stem Cells for Articular Surface Regeneration.
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氟酮乙醇苷是TGF-β3相关的软骨形成的有效协同因素，用于关节表面再生。
DOI：
10.1002/jbmr.2502
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Kuboki T
中科院分区：
文献类型：
--
作者：
Hara ES;Ono M;Pham HT;Sonoyama W;Kubota S;Takigawa M;Matsumoto T;Young MF;Olsen BR;Kuboki T
关节软骨修复仍然是一个具有挑战性的问题。基于高通量筛选和功能分析，我们发现醋酸氟轻松（FA）能显著促进转化生长因子β 3（TGF-β3）介导的人骨髓间充质干细胞（hBMSCs）向软骨细胞的分化。在免疫功能低下小鼠膝关节软骨缺损模型中，FA/TGF-β3处理的hBMSCs移植可完全修复关节面。细胞内途径的分析表明，FA增强TGF-β3诱导的Smad 2和Smad 3的磷酸化。此外，我们进行了通路阵列，发现FA激活mTORC 1/AKT通路。用雷帕霉素化学抑制mTORC 1实质上抑制了FA效应，并且抑制AKT完全抑制了hBMSCs的软骨形成。米非司酮抑制糖皮质激素受体也抑制FA的作用，提示FA与糖皮质激素受体结合有关。与其他糖皮质激素（曲安奈德（TA）和地塞米松（DEX））的比较分析显示FA修复关节软骨手术缺损的独特能力。细胞内通路分析显示，FA和TA高度激活mTORC 1/AKT通路和糖皮质激素受体，但DEX激活程度较低。总的来说，这些结果显示FA增强TGF-β3介导的软骨形成的独特能力，并表明FA/TGF-β3组合可用作体外软骨形成的主要诱导剂。此外，FA/TGF-β3可潜在地应用于临床环境中，以提高基于干细胞的软骨分化的再生方法的效率。
Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) strongly enhances transforming growth factor beta 3 (TGF-β3)-mediated 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 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 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 mTORC1/AKT pathway and glucocorticoid receptor was highly activated with FA and TA, but to a less extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-mediated 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.
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DOI：
10.1073/pnas.1210422109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Diekman, Brian O.;Christoforou, Nicolas;Guilak, Farshid
通讯作者：
Guilak, Farshid
影响因子：
10.8
作者：
Holland, TA;Tabata, Y;Mikos, AG
通讯作者：
Mikos, AG
影响因子：
3.7
作者：
Hara ES;Ono M;Eguchi T;Kubota S;Pham HT;Sonoyama W;Tajima S;Takigawa M;Calderwood SK;Kuboki T
通讯作者：
Kuboki T
影响因子：
168.9
作者：
Coombes, Brooke K.;Bisset, Leanne;Vicenzino, Bill
通讯作者：
Vicenzino, Bill
影响因子：
4.2
作者：
Farkas, Boglarka;Kvell, Krisztian;Bardos, Tamas
通讯作者：
Bardos, Tamas