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

项目总结/摘要 骨髓间充质干细胞（MSCs）具有多向分化潜能，可以通过体外培养或诱导分化为多种细胞。 诱导分化成成骨细胞和脂肪细胞。骨髓间充质干细胞被认为是 对骨骼中的成骨细胞和脂肪细胞都有影响。由于对这两种血统的承诺是相互排斥的， MSC的成骨分化需要协调抑制成脂分化。老化- MSC命运定型和骨形成的相关功能障碍与骨质疏松症有关， 牙周炎和其他代谢性骨疾病。骨质疏松症是最常见的代谢性骨病， 并且是我们老龄化人口中发病率和死亡率的主要原因。在骨质疏松症和骨骼衰老中， 已经观察到MSC的异常谱系分化导致骨髓脂肪组织增加， (MAT)以骨形成为代价的累积。因此，了解分子机制 控制MSC命运决定对于开发新的治疗策略 骨质疏松症和其他慢性骨疾病。过氧化物酶体增殖物激活受体-γ共激活因子1 （PGC-1 β）是肝脏、骨骼肌、 然而，其在骨稳态和代谢中的作用仍有待研究。在这 再次提交时，我们发现PGC-1 β的丢失不仅加速了骨丢失， 在肥胖和衰老小鼠中的蓄积。此外，Pgc-1的特异性缺失可导致多能干细胞中Pgc-1的缺失。 在骨质疏松症中，间充质细胞显著加速MAT积累并损害骨形成。 PGC-1 β的缺失降低了胞浆β-catenin的水平，并损害了Taz的表达，这表明PGC-1 β的缺失可能是导致Taz表达减少的原因之一。 调节MSC命运决定和骨形成。此外，我们发现， PGC-1在人MSC老化过程中的表达。基于这些令人兴奋的发现，我们假设， PGC-1 β在MSC命运决定和骨形成中起关键作用。为了验证我们的假设，我们建议 以下三个具体目标：1）确定PGC-1 β是否内在地调节成骨分化， 骨质疏松症和骨骼衰老中的MSC和骨形成; 2）确定PGC-1 β是否内在地调节 骨髓间充质干细胞在骨质疏松和骨骼衰老中的成脂分化; 3）探讨 PGC-1 β调控MSC成骨和成脂定向的分子机制。 我们研究的新发现可能会确定一种调节MSC命运决定和骨形成的新因子。 因此，为骨质疏松症和MSC介导的颅面神经损伤提供了一个有前途的治疗靶点。 骨再生

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.