Adenosine Receptor Subtype Expression and Activation Influence the Differentiation of Mesenchymal Stem Cells to Osteoblasts and Adipocytes
Adenosine Receptor Subtype Expression and Activation Influence the Differentiation of Mesenchymal Stem Cells to Osteoblasts and Adipocytes
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DOI：
10.1002/jbmr.424
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发表时间：
2011-09-01
影响因子：
6.2
通讯作者：
Evans, Bronwen A. J.
中科院分区：
文献类型：
--
作者：
Gharibi, Borzo;Abraham, Anju A.;Evans, Bronwen A. J.
成骨细胞和脂肪细胞从一个共同的前体细胞，间充质干细胞（MSC）分化而来。众所周知，腺苷通过四种腺苷受体亚型发出信号，值得注意的是，最近的研究结果表明，这些亚型可能在MSC分化中发挥作用。因此，我们研究了MSCs向成骨细胞和脂肪细胞分化过程中腺苷受体的表达和激活。A(2B)R在MSCs中占主导地位，其表达和活性在成骨细胞分化早期短暂上调。A(2B)R的激活和过表达均诱导成骨相关基因[Runx2和碱性磷酸酶（ALP）]的表达，以及ALP的活性，刺激使成骨细胞矿化增加。在成骨细胞分化的后期，A(2A)R的表达上调，当其激活刺激ALP活性时。MSCs向脂肪细胞的分化伴随着A(1)R和A(2A)R表达的显著增加，它们的激活与脂肪形成的增加有关。A(2A)R表达增强足以促进脂肪细胞相关基因（PPAR γ和C/EBP α）的表达，其激活导致脂肪细胞分化和脂质积累增加。相比之下，A(1)R主要参与脂肪细胞的成脂活性，而不是脂肪细胞的分化。这些结果表明腺苷受体的差异表达参与了骨髓间充质干细胞的谱系特异性分化。因此，我们得出结论，治疗与这些谱系分化和功能失衡相关的疾病的有效策略应该包括靶向腺苷受体信号通路。具体来说，这些研究途径将有助于预防或治疗骨质不足或脂肪细胞过多形成的疾病。(C) 2011年美国骨与矿物研究学会。
Osteoblasts and adipocytes differentiate from a common precursor cell, the mesenchymal stem cell (MSC). Adenosine is known to signal via four adenosine receptor subtypes, and significantly, recent findings indicate that these may play a role in MSC differentiation. We therefore investigated adenosine receptor expression and activation during the differentiation of MSCs to osteoblasts and adipocytes. The A(2B)R was dominant in MSCs, and its expression and activity were transiently upregulated at early stages of osteoblastic differentiation. Both activation and overexpression of A(2B)R induced the expression of osteoblast-related genes [Runx2 and alkaline phosphatase (ALP)], as well as ALP activity, and stimulation increased osteoblast mineralization. The expression of A(2A)R was upregulated during later stages of osteoblastic differentiation, when its activation stimulated ALP activity. Differentiation of MSCs to adipocytes was accompanied by significant increases in A(1)R and A(2A)R expression, and their activation was associated with increased adipogenesis. Enhanced A(2A)R expression was sufficient to promote expression of adipocyte-related genes (PPAR gamma and C/EBP alpha), and its activation resulted in increased adipocytic differentiation and lipid accumulation. In contrast, the A(1)R was involved mainly in lipogenic activity of adipocytes rather than in their differentiation. These results show that adenosine receptors are differentially expressed and involved in lineage-specific differentiation of MSCs. We conclude, therefore, that fruitful strategies for treating diseases associated with an imbalance in the differentiation and function of these lineages should include targeting adenosine receptor signal pathways. Specifically, these research avenues will be useful in preventing or treating conditions with insufficient bone or excessive adipocyte formation. (C) 2011 American Society for Bone and Mineral Research.