Molecular Regulation of MSC fate Decision and Bone Formation by PGC-1a

项目摘要/摘要 骨髓间充质干细胞(MSCs)具有多向分化潜能，可 诱导分化为成骨细胞和脂肪细胞。MSCs被认为是共同的祖细胞 对于骨骼中的成骨细胞和脂肪细胞都是如此。由于对这两个谱系的承诺是相互排斥的， MSCs的成骨分化需要协同抑制成脂分化。老化-- 与MSC命运承诺和骨形成相关的功能障碍与骨质疏松有关， 牙周炎和其他代谢性骨骼疾病。骨质疏松症是最常见的代谢性骨病， 是我国老龄化人口发病率和死亡率的主要原因。在骨质疏松和骨骼老化方面， 已观察到骨髓间充质干细胞异常的谱系分化导致骨髓脂肪组织增多。 (垫)以骨形成为代价的堆积。因此，理解分子机制 控制MSC命运的决定对于开发新的治疗策略至关重要 骨质疏松症等慢性骨病。过氧化物酶体增殖物激活受体-γ共激活物1 (pGC-1)是肝脏、骨骼肌线粒体生物发生和氧化代谢的主要调节因子。 然而，大脑和心脏在骨骼动态平衡和新陈代谢中的作用仍有待研究。在这 重新提交，我们发现pGC-1的丢失不仅加速了骨丢失，而且增加了MAT 骨质疏松症和衰老小鼠体内的蓄积。此外，pGC-1在多能性基因中的特异性缺失 间充质细胞在骨质疏松时显著加速MAT堆积和受损的骨形成。 PGC-1的缺失降低了细胞内β-连环蛋白的水平，并损害了TAZ的表达，提示PGC-1 调节MSC的命运决定和骨形成。此外，我们发现， 衰老过程中人骨髓间充质干细胞pGC-1的表达。基于这些令人兴奋的发现，我们假设 PGC-1在骨髓间充质干细胞的命运决定和骨形成中起关键作用。为了检验我们的假设，我们建议 以下三个特定目的：1)确定pGC-1是否内在地调节成骨细胞的分化 骨髓间充质干细胞与骨质疏松症和骨老化中的骨形成；2)确定pGC-1是否具有内在调节作用 骨髓间充质干细胞在骨质疏松和骨老化中的成脂分化；3)探讨骨髓间充质干细胞在骨质疏松症和骨老化中的成脂作用 前列腺素C-1调控骨髓间充质干细胞成骨和成脂的分子机制 我们研究的新发现可能确定一个新的因素，调节MSC的命运决定和骨骼 形成，从而为骨质疏松症和MSC介导的颅面部提供了一个有前途的治疗靶点 骨骼再生。

Project Summary/Abstract Bone marrow mesenchymal stromal/stem cells (MSCs) have multiple differentiation potentials and can be induced to differentiate into osteoblasts and adipocytes. MSCs are believed to be the common progenitors for both osteoblasts and adipocytes in bone. As commitment to these two lineages is mutually exclusive, the osteogenic differentiation of MSCs requires coordinated inhibition of the adipogenic differentiation. Aging- related dysfunctions of MSC fate commitment and bone formation have been related to osteoporosis, periodontitis and other metabolic bone diseases. Osteoporosis is the most common metabolic bone disease, and is a leading cause of morbidity and mortality in our aging population. In osteoporosis and skeletal aging, it has been observed that aberrant lineage differentiation of MSCs leads to increasing marrow adipose tissue (MAT) accumulation at the expense of bone formation. Therefore, understanding the molecular mechanisms that control MSC fate determination is critical for developing novel therapeutic strategies for treating osteoporosis and other chronic bone diseases. Peroxisome proliferator-activated receptor-γ coactivators 1 (PGC-1) is a master regulator of mitochondrial biogenesis and oxidative metabolism in liver, skeletal muscle, brain and the heart, however, its role in bone homeostasis and metabolism remains to be investigated. In this resubmission, we discovered that loss of PGC-1 not only accelerated bone loss, but also enhanced MAT accumulation in osteoporotic and aging mice. Moreover, the specific deletion of Pgc-1 in multipotent mesenchymal cells significantly accelerated MAT accumulation and impaired bone formation in osteoporosis. Loss of PGC-1 reduced cytosolic β-catenin levels and impaired Taz expression, suggesting that PGC-1 regulates MSC fate decision and bone formation. In addition, we found that there was a dramatic decrease in PGC-1 expression in human MSCs during aging. Based on these exciting findings, we hypothesize that PGC-1 plays a critical role in MSC fate decision and bone formation. To test our hypothesis, we propose the following three specific aims: 1) Determine if PGC-1 intrinsically regulates osteogenic differentiation of MSCs and bone formation in osteoporosis and skeletal aging; 2) Determine if PGC-1 intrinsically regulates adipogenic differentiation of MSCs from bone marrow in osteoporosis and skeletal aging; and 3) Explore the molecular mechanisms by which PGC-1 regulates the osteogenic and adipogenic commitment of MSCs. New findings from our studies may identify a novel factor that regulates MSC fate decision and bone formation, and thus presents a promising therapeutic target for osteoporosis and MSC-mediated craniofacial bone regeneration.