OXIDIZED LIPIDS, AGE-RELATED BONE LOSS AND ITS REVERSAL BY INTERMITTENT PTH

氧化脂质、与年龄相关的骨质流失及其通过间歇性 PTH 逆转

• 批准号: 7560561
• 负责人: Robert L Jilka
• 金额: $ 22.03万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7560561
• 关键词: Acetylcysteine; Adenoviruses; Adipocytes; Adverse effects; Age; Age-Months; Age-Related Bone Loss; Alleles; Anabolism; Antioxidants; Apoptosis; Apoptotic; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Architecture; C57BL/6 Mouse; Collagen; Condition; Congenic Mice; Cysteine; DBA/2 Mouse; Daily; Dependence; Development; Elderly; Enzymes; Event; Exhibits; Female; Fracture; Funding; GW9662; Genes; Glutathione Reductase; Hormones; In Vitro; Knockout Mice; Knowledge; Ligands; Lipid Peroxidation; Marrow; Measurement; Measures; Mediating; Mesenchymal Stem Cells; Mus; Numbers; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Oxidative Stress; Oxidoreductase; Parathyroid Hormones; Polyunsaturated Fatty Acids; Prevalence; Prevention; Process; Production; Protein Overexpression; Rate; Reactive Oxygen Species; Research Personnel; Resistance; Role; Secondary to; Skeletal system; Testing; Transcript; Treatment Efficacy; Work; adipocyte differentiation; age related; aged; attenuation; base; bone; bone cell; bone loss; cell type; day; genetic manipulation; human PTH protein; in vivo; inhibitor/antagonist; lipid biosynthesis; oxidized lipid; progenitor; promoter; recombinase; response

Age-related bone loss is due in part to a decrease in osteoblast number. During the previous funding period it was found that activation of PPARy caused bone loss by stimulating the development of adipocytes at the expense of osteoblasts from their common multipotential mesenchymal stem cell progenitor, and by increasing the apoptosis of preosteoblasts. Oxidized lipid ligands of PPARy are generated by the actions of reactive oxygen species (ROS) and/or 12,15-lipoxygenase (Alox15) on linoleic and arachidonic acid. Increased Alox15 expression has been associated with decreased bone mass and strength, and evidence leading to the development of this application revealed an increase in the level of oxidized lipids in murine bone between 8 and 31 months of age. These changes were associated with loss of bone mass and strength, decreased bone formation rate, increased osteoblast and osteocyte apoptosis, and elevated levels of PPARy and Alox15. Reversal of age-related bone loss has been achieved by daily administration of parathyroid hormone (PTH), but the efficacy of this therapy is variable for unknown reasons. In view of evidence that the anabolic effect of PTH is due at least in part to attenuation of osteoblast apoptosis, PTH may reverse the increased osteoblast apoptosis seen in aged mice. The hormone may also increase osteoblast production by inhibiting PPARy activity. The above observations form the basis of the hypothesis that PPARy is increasingly activated by oxidized lipids with advancing age, secondary to elevated levels of ROS and Alox15. Hence, age-related bone loss is due, at least in part, to increased adipogenesis at the expense of osteoblastogenesis and increased apoptosis of osteoblast progenitors. As a corollary, PTH is a rational and especially efficacious treatment for age-related osteoporosis because it counteracts the PPARymediated adverse effects of oxidized lipids and ROS on bone. To test this hypothesis, the role of oxidized lipids generated by Alox15 in age-related bone loss will be examined in vivo by pharmacologic and genetic manipulation of the enzyme and subsequent measurement of bone mass, architecture, strength, osteoblast apoptosis, and bone formation rate (Aim 1). In addition, in vitro studies will be done to distinguish between PPARy-dependent and PPARy-independent effects of Alox15-derived oxidized lipids on osteoblast progenitors (Aim 2). Finally, studies will be performed to investigate whether intermittent administration of PTH to aged mice will specifically reverse the negative skeletal effects of increased oxidized lipids and ROS and thereby increase bone mass (Aim 3). This work should advance knowledge of how the elderly develop osteoporosis and bone fractures. Furthermore, it should provide a better understanding of how to optimize the treatment of this condition.

与年龄相关的骨质流失部分是由于成骨细胞数量减少。在上一个资金期间 发现PPARY的激活通过刺激脂肪细胞在 从其常见的多能间充质干细胞祖细胞中的成骨细胞支出，并通过 增加遗前细胞的细胞凋亡。 PPARY的氧化脂质配体是由 亚油酸和花生四烯酸上的活性氧（ROS）和/或12,15-脂氧合酶（Alox15）。 ALOX15表达增加与骨骼质量和强度降低有关，证据 导致该应用的开发显示鼠中氧化脂质的水平有所增加 8至31个月大的骨头。这些变化与骨骼质量的损失有关 强度，骨形成率降低，成骨细胞和骨细胞凋亡增加以及水平升高 PPARY和ALOX15。通过每天给药，已经实现了与年龄相关的骨质流失 甲状旁腺激素（PTH），但由于未知原因，该疗法的功效是可变的。鉴于 PTH的合成代谢作用至少部分归因于成骨细胞凋亡，PTH的证据 可能会扭转老年小鼠中观察到的成骨细胞凋亡的增加。激素也可能增加 通过抑制PPARY活性来产生成骨细胞。上述观察构成了假设的基础 随着年龄的增长，这种氧化的脂质越来越多地激活 ROS和ALOX15。因此，与年龄相关的骨质流失至少部分是由于在 成骨细胞生成的费用和成骨细胞祖细胞的凋亡增加。作为推论，pth是 对于年龄相关的骨质疏松症，理性，特别有效的治疗 氧化脂质和ROS对骨骼的不利影响。为了检验这一假设，氧化的作用 Alox15在年龄有关的骨质流失中产生的脂质将在体内通过药物和遗传检查 操纵酶的操纵以及随后的骨骼质量，结构，强度，成骨细胞的测量 凋亡和骨形成率（AIM 1）。另外，将进行体外研究以区分 Alox15衍生的氧化脂质对成骨细胞的PPARY依赖性和PPARY独立的作用 祖先（目标2）。最后，将进行研究以调查是否间歇性给药 PTH至老年小鼠将特别扭转氧化脂质和ROS增加的负骨骼效应 从而增加骨骼质量（AIM 3）。这项工作应提高老年人如何发展的知识 骨质疏松和骨折。此外，它应该更好地了解如何优化 这种情况的处理。