A Comprehensive Analysis of the Dual Roles of BMPs in Regulating Adipogenic and Osteogenic Differentiation of Mesenchymal Progenitor Cells

Pluripotent mesenchymal stem cells (MSCs) are bone marrow stromal progenitor cells that can differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. Several signaling pathways have been shown to regulate the lineage commitment and terminal differentiation of MSCs. Here, we conducted a comprehensive analysis of the 14 types of bone morphogenetic protein (BMPs) for their abilities to regulate multilineage specific differentiation of MSCs. We found that most BMPs exhibited distinct abilities to regulate the expression of Runx2, Sox9, MyoD, and PPAR gamma 2. Further analysis indicated that BMP-2, BMP-4, BMP-6, BMP-7, and BMP-9 effectively induced both adipogenic and osteogenic differentiation in vitro and in vivo. BMP-induced commitment to osteogenic or adipogenic lineage was shown to be mutually exclusive. Overexpression of Runx2 enhanced BMP-induced osteogenic differentiation, whereas knockdown of Runx2 expression diminished BMP-induced bone formation with a decrease in adipocyte accumulation in vivo. Interestingly, overexpression of PPAR gamma 2 not only promoted adipogenic differentiation, but also enhanced osteogenic differentiation upon BMP-2, BMP-6, and BMP-9 stimulation. Conversely, MSCs with PPAR gamma 2 knockdown or mouse embryonic fibroblasts derived from PPAR gamma 2(-/-) mice exhibited a marked decrease in adipogenic differentiation, coupled with reduced osteogenic differentiation and diminished mineralization upon BMP-9 stimulation, suggesting that PPAR gamma 2 may play a role in BMP-induced osteogenic and adipogenic differentiation. Thus, it is important to understand the molecular mechanism behind BMP-regulated lineage divergence during MSC differentiation, as this knowledge could help us to understand the pathogenesis of skeletal diseases and may lead to the development of strategies for regenerative medicine.

多能间充质干细胞（MSCs）是骨髓基质祖细胞，可分化为成骨、成软骨、成脂和成肌谱系。已有研究表明，若干信号通路可调节MSCs的谱系定向和终末分化。在此，我们对14种骨形态发生蛋白（BMPs）调节MSCs多谱系特异性分化的能力进行了全面分析。我们发现，大多数BMPs在调节Runx2、Sox9、MyoD和PPARγ2的表达方面表现出不同的能力。进一步分析表明，BMP - 2、BMP - 4、BMP - 6、BMP - 7和BMP - 9在体外和体内均可有效诱导成脂和成骨分化。BMP诱导的成骨或成脂谱系定向是相互排斥的。Runx2的过表达增强了BMP诱导的成骨分化，而Runx2表达的敲低则减少了BMP诱导的体内骨形成，同时脂肪细胞积累减少。有趣的是，PPARγ2的过表达不仅促进成脂分化，而且在BMP - 2、BMP - 6和BMP - 9刺激下还增强成骨分化。相反，PPARγ2敲低的MSCs或来自PPARγ2（-/-）小鼠的胚胎成纤维细胞在BMP - 9刺激下成脂分化显著减少，同时成骨分化降低且矿化减少，这表明PPARγ2可能在BMP诱导的成骨和成脂分化中发挥作用。因此，了解MSCs分化过程中BMP调节谱系分化背后的分子机制非常重要，因为这一知识有助于我们理解骨骼疾病的发病机制，并可能促使再生医学策略的发展。