Different consequences of cellular aging in cortical versus cancellous bone- Resubmission

皮质骨与松质骨细胞老化的不同后果 - Resubmission

基本信息

批准号：
10544757
负责人：
Maria Jose Almeida
金额：
$ 38.36万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544757
关键词：
Adipocytes Age Age-Related Bone Loss Aging Apoptosis Attenuated Bone Marrow Bone Resorption Bone remodeling CDKN1A gene CDKN2A gene Cell Aging Cell Cycle Arrest Cell Cycle Regulation Cell Lineage Cells DNA Damage Disease Exhibits Fracture GATA4 gene Human In Vitro Inflammatory Knowledge Label Laboratories Molecular Mus NF-kappa B Organ Culture Techniques Osteoblasts Osteocytes Osteogenesis Osteoporosis Oxidative Stress Induction Pathway interactions Phenotype Porosity Production Resistance SOD2 gene Skeleton TNFSF11 gene TP53 gene Testing Thinness Time Tissues Transgenes Transgenic Organisms Up-Regulation Vertebral column Woman Work age related aged bone bone loss bone mass cell type cortical bone cytokine fragility fracture functional decline human old age (65+)inhibitor long bone loss of function men osteoprogenitor cell overexpression pharmacologic prevent progenitor red fluorescent protein response senescence skeletal substantia spongiosa therapy development young adult

Adipocytes Age Age-Related Bone Loss Aging Apoptosis Attenuated Bone Marrow Bone Resorption Bone remodeling CDKN1A gene CDKN2A gene Cell Aging Cell Cycle Arrest Cell Cycle Regulation Cell Lineage Cells DNA Damage Disease Exhibits Fracture GATA4 gene Human In Vitro Inflammatory Knowledge Label Laboratories Molecular Mus NF-kappa B Organ Culture Techniques Osteoblasts Osteocytes Osteogenesis Osteoporosis Oxidative Stress Induction Pathway interactions Phenotype Porosity Production Resistance SOD2 gene Skeleton TNFSF11 gene TP53 gene Testing Thinness Time Tissues Transgenes Transgenic Organisms Up-Regulation Vertebral column Woman Work age related aged bone bone loss bone mass cell type cortical bone cytokine fragility fracture functional decline human old age (65+)inhibitor long bone loss of function men osteoprogenitor cell overexpression pharmacologic prevent progenitor red fluorescent protein response senescence skeletal substantia spongiosa therapy development young adult

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项目摘要

Project Summary/Abstract Aging is responsible for the majority of fractures in both women and men. The cellular changes in the skeleton of aged mice are similar to those observed in aged humans. In mice, trabecular bone loss is associated with low bone remodeling, while cortical thinning and porosity are associated with high bone remodeling. These findings suggest that different molecular mechanisms underlie the bone loss in these two compartments. Cellular senescence contributes to the functional decline of multiple tissues with age and DNA damage is a major cause of senescence. DNA damage causes senescence via activation of p53 and up-regulation of the cell cycle inhibitor p21 and/or p16. DNA damage also causes accumulation of the transcription factor GATA4, which promotes the senescence associated secretory phenotype (SASP). Systemic clearance of senescent cells delays several age- associated disorders and increases bone mass in old mice. We have shown that the number of osteoprogenitors in murine bone marrow declines with age and that these cells have increased markers of senescence. Cortical osteocytes also exhibit increased markers of senescence in aged mice and this is associated with elevated production of RANKL. Induction of senescence in bone organ cultures by DNA damage is sufficient to increase GATA4 and RANKL production. Moreover, overexpression of GATA4 in vitro is sufficient to increase RANKL and other components of the SASP. Administration of senolytics to old mice attenuates markers of senescence in osteoprogenitors and osteocytes. Notably, mice lacking RANKL in osteocytes are protected from the loss of cortical but not trabecular bone with age. We hypothesize that activation of p53/p21 in osteoprogenitors causes their senescence and thereby decreases osteoblast number and bone formation and that accumulation of senescent osteocytes in cortical, but not trabecular, bone increases RANKL and bone resorption via GATA4 stimulation. In Aim 1 we will determine whether DNA damage in osteoblast lineage cells is sufficient to induce senescence and reduce bone mass. To do this, we will generate mice with oxidative stress- induced senescence in either the entire osteoblast lineage or only in mature osteoblasts and osteocytes. Administration of the senolytic PZ15227 will reveal what components of the phenotype are due to senescence. In Aim 2 we will determine the contribution of the p53/p21 pathway in osteoprogenitors to skeletal aging by aging mice with p53 or p21 loss-of-function. In Aim 3 we will investigate the differential contribution of senescent osteocytes to increased bone resorption in trabecular versus cortical bone with age by aging mice with GATA4 loss-of-function in osteocytes. We will also quantify osteocyte senescence in cortical versus trabecular bone and determine whether senescent osteocytes express higher levels of RANKL. Successful completion of these studies should establish for the first time whether senescence of osteoprogenitors and osteocytes contributes to the loss of bone mass with age, and help clarify different aging mechanisms in cortical versus trabecular bone.

项目摘要/摘要衰老是男女的大部分骨折。骨骼的细胞变化老年小鼠的年龄与在老年人中观察到的小鼠相似。在小鼠中，小梁骨质流失与低相关骨骼重塑，而皮质变薄和孔隙率与高骨重塑有关。这些发现表明这两个隔室的骨质流失是不同的分子机制。细胞衰老有助于随着年龄的年龄和DNA损伤的多个组织的功能下降是一个主要原因衰老。 DNA损伤通过激活p53和细胞周期抑制剂的上调导致衰老 p21和/或p16。 DNA损伤还会导致转录因子GATA4的积累，从而促进衰老相关的分泌表型（SASP）。衰老细胞的全身清除延迟了几个年龄 - 相关疾病并增加旧小鼠的骨骼量。我们已经证明了骨化剂的数量在鼠骨骨髓中随着年龄的增长而下降，这些细胞的衰老标记增加。皮质骨细胞在老年小鼠中也表现出增加的衰老标记物，这与升高有关 Rankl的生产。通过DNA损伤诱导骨骼器官培养的衰老足以增加 GATA4和RANKL生产。此外，体外GATA4的过表达足以增加RANKL 和SASP的其他组成部分。对老鼠的塞溶剂给药减弱了衰老的标志在骨基因和骨细胞中。值得注意的是，在骨细胞中缺乏RANKL的小鼠受到保护随着年龄的增长，皮质的但不是小梁骨。我们假设p53/p21在破骨者中的激活引起衰老，从而减少成骨细胞的数量和骨形成，并且皮质中但不是小梁中衰老骨细胞的积累通过GATA4刺激吸收。在AIM 1中，我们将确定成骨细胞中的DNA损伤是否损伤足以诱导衰老并减少骨骼。为此，我们将产生具有氧化应激的小鼠在整个成骨细胞谱系中或仅在成熟的成骨细胞和骨细胞中诱导衰老。鼻溶性PZ15227的给药将揭示表型的哪些组成部分是由于衰老引起的。在AIM 2中，我们将确定骨化器中p53/p21途径在衰老中对骨骼老化的贡献具有p53或p21功能丧失的小鼠。在AIM 3中，我们将研究衰老的差异贡献通过gata4衰老的小鼠，小梁与皮质骨的骨吸收增加的骨细胞增加了骨吸收骨细胞功能丧失。我们还将定量皮质骨与小梁骨的骨细胞衰老和确定衰老骨细胞是否表达较高的RANKL水平。这些成功完成研究应首次确定骨基因生成剂和骨细胞的衰老是否有助于随着年龄的增长，骨骼质量的丧失，并有助于阐明皮质与小梁骨的不同衰老机制。