Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
J Biol Chem. 2012 May 4;287(19):15718-27. doi: 10.1074/jbc.M112.344994. Epub 2012 Mar 8.
The differentiation of osteoblasts from their precursors, mesenchymal stem cells, is an important component of bone homeostasis as well as fracture healing. The A2B adenosine receptor (A2BAR) is a Gα(s)/α(q)-protein-coupled receptor that signals via cAMP. cAMP-mediated signaling has been demonstrated to regulate the differentiation of mesenchymal stem cells (MSCs) into various skeletal tissue lineages. Here, we studied the role of this receptor in the differentiation of MSCs to osteoblasts. In vitro differentiation of bone marrow-derived MSCs from A2BAR KO mice resulted in lower expression of osteoblast differentiation transcription factors and the development of fewer mineralized nodules, as compared with WT mice. The mechanism of effect involves, at least partially, cAMP as indicated by experiments involving activation of the A2BAR or addition of a cAMP analog during differentiation. Intriguingly, in vivo, microcomputed tomography analysis of adult femurs showed lower bone density in A2BAR KO mice as compared with WT. Furthermore, A2BAR KO mice display a delay in normal fracture physiology with lower expression of osteoblast differentiation genes. Thus, our study identified the A2BAR as a new regulator of osteoblast differentiation, bone formation, and fracture repair.
成骨细胞由其前体细胞间充质干细胞分化而来，是骨稳态和骨折愈合的重要组成部分。A2B 腺苷受体（A2BAR）是一种 Gα(s)/α(q)-蛋白偶联受体，通过 cAMP 信号转导。已经证明 cAMP 介导的信号转导可调节间充质干细胞（MSCs）向各种骨骼组织谱系的分化。在这里，我们研究了该受体在间充质干细胞向成骨细胞分化中的作用。与 WT 小鼠相比，从 A2BAR KO 小鼠骨髓来源的 MSC 体外分化导致成骨细胞分化转录因子的表达降低，矿化结节的形成减少。作用机制至少部分涉及 cAMP，这可以通过在分化过程中激活 A2BAR 或添加 cAMP 类似物的实验来证明。有趣的是，体内，对成年股骨的 microCT 分析表明，与 WT 小鼠相比，A2BAR KO 小鼠的骨密度较低。此外，A2BAR KO 小鼠在正常骨折生理过程中表现出延迟，成骨细胞分化基因的表达降低。因此，我们的研究确定 A2BAR 是成骨细胞分化、骨形成和骨折修复的新调节剂。
