Loss of Gsα Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast Precursors
Loss of Gsα Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast Precursors
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DOI：
10.1002/jbmr.2270
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发表时间：
2014-11-01
影响因子：
6.2
通讯作者：
Wu, Joy Y.
中科院分区：
文献类型：
--
作者：
Sinha, Partha;Aarnisalo, Piia;Wu, Joy Y.
在人类中，衰老和糖皮质激素治疗与骨量减少和骨髓肥胖增加有关，这表明成骨细胞和脂肪细胞的分化可能受到协调调节。在骨髓中，成骨细胞和脂肪细胞都来源于间充质祖细胞，但指导间充质祖细胞定向成骨细胞与脂肪细胞谱系的机制尚未完全确定。异源三聚体G蛋白亚基G（s）激活包括甲状旁腺激素受体在内的几种G蛋白偶联受体下游的蛋白激酶A信号传导，并在调节骨量中起关键作用。在这里，我们发现，在早期成骨细胞前体中靶向去除G（s），而不是在分化的骨细胞中，导致骨髓脂肪细胞的急剧增加。突变小鼠的间充质祖细胞数量总体上减少，定向为脂肪细胞谱系的祖细胞比例增加。此外，定向成骨细胞谱系的细胞在体外和体内均保留成脂潜力。这些发现对开发治疗方法以指导间充质祖细胞向成骨细胞谱系的承诺具有临床意义。(c)2014年美国骨与矿物质研究学会
In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit G(s) activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of G(s) in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage. (c) 2014 American Society for Bone and Mineral Research