Center for Endocrine and Diabetes Sciences, School of Medicine, Cardiff University, Cardiff, UK.
J Bone Miner Res. 2011 Sep;26(9):2112-24. doi: 10.1002/jbmr.424.
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 (PPARγ and C/EBPα), 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.
成骨细胞和脂肪细胞由共同的前体细胞，间充质干细胞（MSC）分化而来。已知腺苷通过四种腺苷受体亚型发挥信号作用，而最近的研究结果表明，这些受体亚型可能在 MSC 分化中发挥作用。因此，我们研究了腺苷受体在 MSC 向成骨细胞和脂肪细胞分化过程中的表达和激活。A2B 受体在 MSC 中占主导地位，其表达和活性在成骨细胞分化的早期阶段短暂上调。A2B 受体的激活和过表达均诱导与成骨细胞相关的基因[Runx2 和碱性磷酸酶（ALP）]的表达，以及 ALP 活性，并刺激成骨细胞矿化。A2A 受体的表达在成骨细胞分化的后期上调，此时其激活刺激 ALP 活性。MSC 向脂肪细胞分化伴随着 A1 受体和 A2A 受体表达的显著增加，其激活与脂肪生成增加有关。增强的 A2A 受体表达足以促进脂肪细胞相关基因（PPARγ 和 C/EBPα）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，A1 受体主要参与脂肪细胞的脂生成活性，而不是其分化。这些结果表明，腺苷受体在 MSC 的谱系特异性分化中差异表达并发挥作用。因此，我们得出结论，治疗与这些谱系的分化和功能失衡相关疾病的富有成效的策略应包括靶向腺苷受体信号通路。具体而言，这些研究途径将有助于预防或治疗骨量不足或脂肪细胞过度形成的疾病。
