Peroxisome Proliferator-Activated Receptor α Facilitates Osteogenic Differentiation in MC3T3-E1 Cells via the Sirtuin 1-Dependent Signaling Pathway.
Peroxisome Proliferator-Activated Receptor α Facilitates Osteogenic Differentiation in MC3T3-E1 Cells via the Sirtuin 1-Dependent Signaling Pathway.
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DOI：
10.14348/molcells.2017.0018
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发表时间：
2017-06-30
影响因子：
3.8
通讯作者：
Pan X
中科院分区：
文献类型：
--
作者：
Gong K;Qu B;Wang C;Zhou J;Liao D;Zheng W;Pan X
2型糖尿病（T2DM）是一种以胰岛素缺乏和高血糖水平为特征的慢性代谢性疾病。T2DM可导致骨质流失和骨折，从而导致糖尿病性骨质疏松。促进成骨细胞成骨分化可有效治疗糖尿病性骨质疏松症。我们之前报道过Sirtuin 1 (Sirt1)，一种NAD+依赖的去乙酰化酶，通过下调过氧化物酶体增殖物激活受体(PPAR) γ促进成骨分化。我们还发现miR-132通过下调Sirt1以PPARβ/δ依赖的方式调节成骨分化。配体激活的转录因子PPARα是过氧化物酶体增殖物激活受体家族的另一种同型，有助于维持骨稳态和促进骨形成。PPARα在成骨分化中的调节作用是否通过Sirt1介导尚不清楚。在本研究中，我们旨在通过使用高糖（HG）和游离脂肪酸（FFA）在MC3T3-E1细胞中模拟T2DM来确定这一作用及其潜在机制。结果表明，HG-FFA显著抑制PPARα、Sirt1的表达和成骨分化，但这些作用被PPARα过表达明显逆转。此外，siSirt1减弱了PPARα对成骨分化的积极作用，表明PPARα以sirt1依赖的方式促进成骨分化。荧光素酶活性测定证实了PPARα与Sirt1之间的相互作用。这些发现表明PPARα通过sirt1依赖的信号通路促进成骨分化。
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by lack of insulin and high glucose levels. T2DM can cause bone loss and fracture, thus leading to diabetic osteoporosis. Promoting osteogenic differentiation of osteoblasts may effectively treat diabetic osteoporosis. We previously reported that Sirtuin 1 (Sirt1), a NAD+-dependent deacetylase, promotes osteogenic differentiation through downregulation of peroxisome proliferator-activated receptor (PPAR) γ. We also found that miR-132 regulates osteogenic differentiation by downregulating Sirt1 in a PPARβ/δ-dependent manner. The ligand-activated transcription factor, PPARα, is another isotype of the peroxisome proliferator-activated receptor family that helps maintain bone homeostasis and promot bone formation. Whether the regulatory role of PPARα in osteogenic differentiation is mediated via Sirt1 remains unclear. In the present study, we aimed to determine this role and the underlying mechanism by using high glucose (HG) and free fatty acids (FFA) to mimic T2DM in MC3T3-E1 cells. The results showed that HG-FFA significantly inhibited expression of PPARα, Sirt1 and osteogenic differentiation, but these effects were markedly reversed by PPARα overexpression. Moreover, siSirt1 attenuated the positive effects of PPARα on osteogenic differentiation, suggesting that PPARα promotes osteogenic differentiation in a Sirt1-dependent manner. Luciferase activity assay confirmed interactions between PPARα and Sirt1. These findings indicate that PPARα promotes osteogenic differentiation via the Sirt1-dependent signaling pathway.