Thyroid Hormone-Induced Hypertrophy in Mesenchymal Stem Cell Chondrogenesis Is Mediated by Bone Morphogenetic Protein-4
Thyroid Hormone-Induced Hypertrophy in Mesenchymal Stem Cell Chondrogenesis Is Mediated by Bone Morphogenetic Protein-4
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DOI：
10.1089/ten.tea.2013.0023
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发表时间：
2014-01-01
影响因子：
4.1
通讯作者：
Mueller, Michael B.
中科院分区：
文献类型：
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作者：
Karl, Alexandra;Olbrich, Norman;Mueller, Michael B.
软骨分化间充质干细胞（MSC）表达肥大生长板软骨细胞的标志物。由于肥大的软骨发生骨化，这是一个关注的应用间充质干细胞在关节软骨组织工程。为了确定引起这种现象的机制，我们使用了一个体外肥大模型，用于差异基因表达分析和功能实验，重点是骨形态发生蛋白（BMP）信号传导。通过转化生长因子β（TGF β）和地塞米松的撤除和三碘甲腺原氨酸的添加，在软骨形成MSC颗粒培养物中诱导肥大。进行BMP及其受体的差异基因表达分析。基于这些结果，使用体外肥大模型来研究重组BMP 4和BMP抑制剂Noggin的作用。肥大的增强可以通过细胞大小、碱性磷酸酶活性和X型胶原沉积的增加清楚地显示。在诱导肥大后，BMP 4和BMP受体1B上调。BMP 4的加入进一步增强了不存在TGF β和地塞米松的情况下的肥大，但在存在TGF β和地塞米松的情况下不存在。甲状腺激素通过上调BMP 4诱导肥大，这种诱导的肥大增强可以被BMP拮抗剂Noggin阻断。BMP信号传导是MSC软骨形成中晚期分化阶段的重要调节剂，甲状腺激素诱导该途径。由于软骨组织工程构建体将在体内暴露于该因子，因此本研究为基于MSC的软骨的生物学提供了重要的见解。此外，工程肥大软骨的可能性可能有助于关键骨缺损修复。
Chondrogenic differentiating mesenchymal stem cells (MSCs) express markers of hypertrophic growth plate chondrocytes. As hypertrophic cartilage undergoes ossification, this is a concern for the application of MSCs in articular cartilage tissue engineering. To identify mechanisms that elicit this phenomenon, we used an in vitro hypertrophy model of chondrifying MSCs for differential gene expression analysis and functional experiments with the focus on bone morphogenetic protein (BMP) signaling. Hypertrophy was induced in chondrogenic MSC pellet cultures by transforming growth factor beta (TGF beta) and dexamethasone withdrawal and addition of triiodothyronine. Differential gene expression analysis of BMPs and their receptors was performed. Based on these results, the in vitro hypertrophy model was used to investigate the effect of recombinant BMP4 and the BMP inhibitor Noggin. The enhancement of hypertrophy could be shown clearly by an increased cell size, alkaline phosphatase activity, and collagen type X deposition. Upon induction of hypertrophy, BMP4 and the BMP receptor 1B were upregulated. Addition of BMP4 further enhanced hypertrophy in the absence, but not in the presence of TGF beta and dexamethasone. Thyroid hormone induced hypertrophy by upregulation of BMP4 and this induced enhancement of hypertrophy could be blocked by the BMP antagonist Noggin. BMP signaling is an important modulator of the late differentiation stages in MSC chondrogenesis and the thyroid hormone induces this pathway. As cartilage tissue engineering constructs will be exposed to this factor in vivo, this study provides important insight into the biology of MSC-based cartilage. Furthermore, the possibility to engineer hypertrophic cartilage may be helpful for critical bone defect repair.