Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton
Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-γ Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton
复制标题
DOI：
10.1074/jbc.m109.023572
复制
发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Jilka, Robert L.
中科院分区：
文献类型：
--
作者：
Almeida, Maria;Ambrogini, Elena;Jilka, Robert L.
随着年龄的增长，小鼠骨量的减少是由于成骨细胞数量减少，并与氧化应激增加和典型Wnt信号减少有关。然而，人们对其潜在机制知之甚少。我们报告了小鼠骨骼中脂质氧化产物4-羟基壬烯醛（4-HNE）的年龄相关增加，以及脂氧合酶和过氧化物酶体增殖激活受体γ (PPAR γ)的表达增加。这些变化以及Wnt信号的减少在4个月大的小鼠中重现，这些小鼠携带高表达的脂肪加氧酶Alox15等位基因。在培养的成骨细胞中添加4-HNE会增加氧化应激，从而将β -catenin从t细胞特异性转录因子转移到叉头盒O （FoxO）转录因子，从而减弱β -catenin对PPAR γ基因表达的抑制作用。氧化脂质作为PPAR γ的配体，促进PPAR γ 2与β -连环蛋白的结合，降低后者的水平，并减弱wnt3a刺激的增殖和成骨细胞分化。此外，氧化脂质和4-HNE刺激成骨细胞凋亡。鉴于氧化脂质在动脉粥样硬化中的作用，脂氧合酶介导的脂质氧化对成骨细胞分化和存活的不利影响可能为动脉粥样硬化与骨质疏松之间的联系提供了机制解释。
Loss of bone mass with advancing age in mice is because of decreased osteoblast number and is associated with increased oxidative stress and decreased canonical Wnt signaling. However, the underlying mechanisms are poorly understood. We report an age-related increase in the lipid oxidation product 4-hydroxynonenal (4-HNE) as well as increased expression of lipoxygenase and peroxisome proliferator-activated receptor-gamma (PPAR gamma) in the murine skeleton. These changes together with decreased Wnt signaling are reproduced in 4-month-old mice bearing a high expressing allele of the lipoxygenase Alox15. The addition of 4-HNE to cultured osteoblastic cells increases oxidative stress, which in turn diverts beta-catenin from T-cell-specific transcription factors to Forkhead box O (FoxO) transcription factors, thereby attenuating the suppressive effect of beta-catenin on PPAR gamma gene expression. Oxidized lipids, acting as ligands of PPAR gamma, promote binding of PPAR gamma 2 to beta-catenin and reduce the levels of the latter, and they attenuate Wnt3a-stimulated proliferation and osteoblast differentiation. Furthermore, oxidized lipids and 4-HNE stimulate apoptosis of osteoblastic cells. In view of the role of oxidized lipids in atherogenesis, the adverse effects of lipoxygenase-mediated lipid oxidation on the differentiation and survival of osteoblasts may provide a mechanistic explanation for the link between atherosclerosis and osteoporosis.