Feigenson Marina, Eliseev Roman A, Jonason Jennifer H, Mills Bradley N, O'Keefe Regis J
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620.
Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620.
J Cell Biochem. 2017 Dec;118(12):4383-4393. doi: 10.1002/jcb.26092. Epub 2017 May 31.
Mesenchymal stromal cells (MSCs) are multipotent progenitors capable of differentiation into osteoblasts and can potentially serve as a source for cell-based therapies for bone repair. Many factors have been shown to regulate MSC differentiation into the osteogenic lineage such as the Cyclooxygenase-2 (COX2)/Prostaglandin E2 (PGE2) signaling pathway that is critical for bone repair. PGE2 binds four different receptors EP1-4. While most studies focus on the role PGE2 receptors EP2 and EP4 in MSC differentiation, our study focuses on the less studied, receptor subtype 1 (EP1) in MSC function. Recent work from our laboratory showed that EP1 mice have enhanced fracture healing, stronger cortical bones, higher trabecular bone volume and increased in vivo bone formation, suggesting that EP1 is a negative regulator of bone formation. In this study, the regulation of MSC osteogenic differentiation by EP1 receptor was investigated using EP1 genetic deletion in EP1 mice. The data suggest that EP1 receptor functions to maintain MSCs in an undifferentiated state. Loss of the EP1 receptor changes MSC characteristics and permits stem cells to undergo more rapid osteogenic differentiation. Notably, our studies suggest that EP1 receptor regulates MSC differentiation by modulating MSC bioenergetics, preventing the shift to mitochondrial oxidative phosphorylation by maintaining high Hif1α activity. Loss of EP1 results in inactivation of Hif1α, increased oxygen consumption rate and thus increased osteoblast differentiation. J. Cell. Biochem. 118: 4383-4393, 2017. © 2017 Wiley Periodicals, Inc.
间充质基质细胞（MSCs）是多能祖细胞，能够分化为成骨细胞，并有可能作为骨修复细胞疗法的来源。许多因素已被证明可调节MSCs向成骨谱系的分化，如环氧化酶-2（COX2）/前列腺素E2（PGE2）信号通路，该通路对骨修复至关重要。PGE2与四种不同的受体EP1-4结合。虽然大多数研究集中在PGE2受体EP2和EP4在MSCs分化中的作用，但我们的研究聚焦于研究较少的受体亚型1（EP1）在MSCs功能中的作用。我们实验室最近的研究表明，EP1基因敲除小鼠的骨折愈合增强、皮质骨更强、小梁骨体积更高且体内骨形成增加，这表明EP1是骨形成的负调节因子。在本研究中，利用EP1基因敲除小鼠研究了EP1受体对MSCs成骨分化的调节作用。数据表明，EP1受体的功能是使MSCs维持在未分化状态。EP1受体的缺失改变了MSCs的特性，使干细胞能够更快地进行成骨分化。值得注意的是，我们的研究表明，EP1受体通过调节MSCs的生物能量学来调节MSCs的分化，通过维持高Hif1α活性来防止向线粒体氧化磷酸化的转变。EP1的缺失导致Hif1α失活，耗氧率增加，从而增加成骨细胞分化。《细胞生物化学杂志》118: 4383 - 4393，2017年。© 2017威利期刊公司。
