A2B Adenosine Receptor Promotes Mesenchymal Stem Cell Differentiation to Osteoblasts and Bone Formation in Vivo
A2B Adenosine Receptor Promotes Mesenchymal Stem Cell Differentiation to Osteoblasts and Bone Formation in Vivo
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DOI：
10.1074/jbc.m112.344994
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发表时间：
2012-05-04
影响因子：
4.8
通讯作者：
Ravid, Katya
中科院分区：
文献类型：
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作者：
Carroll, Shannon H.;Wigner, Nathan A.;Ravid, Katya
成骨细胞从其前体间充质干细胞分化为成骨细胞是骨稳态和骨折愈合的重要组成部分。A2 B腺苷受体（A2 BAR）是一种G alpha（s）/alpha（q）-蛋白偶联受体，通过cAMP发出信号。cAMP介导的信号传导已被证明可调节间充质干细胞（MSC）分化为各种骨骼组织谱系。在这里，我们研究了这种受体在骨髓间充质干细胞分化成骨细胞的作用。与WT小鼠相比，A2 BAR KO小鼠骨髓来源的MSC的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，如涉及A2 BAR活化或在分化期间添加cAMP类似物的实验所示。有趣的是，在体内，成年股骨的显微计算机断层扫描分析显示，与WT相比，A2 BAR KO小鼠的骨密度较低。此外，A2 BAR KO小鼠表现出正常骨折生理学延迟，成骨细胞分化基因表达较低。因此，我们的研究确定了A2 BAR作为成骨细胞分化、骨形成和骨折修复的新调节因子。
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 G alpha(s)/alpha(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.