Molecular mechanisms of glucocorticoid-induced bone loss

糖皮质激素引起的骨丢失的分子机制

• 批准号: 10084209
• 负责人: CHARLES A O'BRIEN
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084209
• 关键词: Address; Albers-Schonberg disease; Apoptosis; Arthritis; Bacterial Artificial Chromosomes; Bone Resorption; Bone Resorption Stimulation; CASP8 gene; Cell Lineage; Cells; Chronic; Complex; DNA Sequence; Development; Gene Deletion; Genes; Genetic; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Graft Rejection; Health; Histologic; Human; Induction of Apoptosis; Inflammation; Inflammatory; Lead; Ligands; Maps; Measures; Mediating; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Patients; Placebos; Process; Production; Regulatory Element; Reporter; Skeleton; Structure; Surface; TNFSF11 gene; Therapeutic Uses; Thick; Tumor necrosis factor receptor 11b; Veterans; WNT Signaling Pathway; Work; base; beta catenin; bone; bone loss; bone mass; bone strength; cell type; cortical bone; effective intervention; fracture risk; long bone; mouse model; novel strategies; patient population; prevent; response; side effect; substantia spongiosa

Glucocorticoid administration is frequently used to suppress inflammation and treat a variety of conditions in the VA patient population. One of the most significant side effects of this therapy is bone loss and increased risk of fracture. We have developed a murine model of glucocorticoid-induced bone loss that mimics many of the structural and histological changes observed in humans. In addition, we have used mice with genetic deletion of the glucocorticoid receptor in specific cell types to identify the targets of glucocorticoid action on the skeleton. We found that deletion of the glucocorticoid receptor from osteoblast lineage cells prevents the stimulation of bone resorption and the suppression of bone formation caused by glucocorticoid administration. However, the molecular mechanisms by which glucocorticoids stimulate bone resorption and suppress bone formation by acting on this cell type remain unclear. Based on preliminary studies, we propose the central hypothesis that glucocorticoids stimulate bone resorption by suppressing expression of osteoprotegerin (OPG) and that they suppress bone formation by antagonizing canonical Wnt signaling. To address this hypothesis we will identify the molecular mechanisms by which glucocorticoids suppress expression of the OPG gene using a combination of large transcriptional reporter constructs and deletion of regulatory sequences from the endogenous OPG gene in cells and mice (Aim 1). We will also determine whether glucocorticoids suppress bone formation by stimulating the apoptosis of osteoblast lineage cells by blocking induction of apoptosis in this cell type. This will be accomplished by deletion of genes essential for apoptosis (Bak, Bax, and Caspase 8) in this cell lineage (Aim 2). Lastly, we will determine whether glucocorticoids suppress bone formation by opposing Wnt signaling by creating mice with constitutive activation of β-catenin in osteoblasts and treating them with exogenous glucocorticoids. If our hypothesis is correct, this maneuver will prevent suppression of bone formation by glucocorticoids (Aim 3). Overall, the proposed studies will clarify the molecular changes by which glucocorticoid excess causes bone loss and may identify novel approaches to prevent this bone loss in patients that require chronic glucocorticoid therapy.

糖皮质激素给药经常用于抑制炎症和治疗糖尿病患者的各种病症。 VA患者人群。这种疗法最显著的副作用之一是骨质流失和增加的风险， 骨折我们已经建立了糖皮质激素诱导的骨丢失的小鼠模型，该模型模拟了许多 在人体内观察到的结构和组织学变化。此外，我们还使用了基因缺失的小鼠， 糖皮质激素受体在特定的细胞类型，以确定目标的糖皮质激素作用的骨骼。 我们发现，成骨细胞系中糖皮质激素受体的缺失阻止了成骨细胞对糖皮质激素受体的刺激。 糖皮质激素给药引起的骨吸收和骨形成抑制。但 糖皮质激素刺激骨吸收和抑制骨形成的分子机制， 对这种细胞类型的作用尚不清楚。基于初步研究，我们提出了中心假设， 糖皮质激素通过抑制骨保护素（OPG）的表达刺激骨吸收， 通过拮抗经典Wnt信号传导抑制骨形成。为了解决这个假设，我们将确定 糖皮质激素联合应用抑制OPG基因表达的分子机制 大的转录报告基因构建体和内源性OPG基因调控序列的缺失 在细胞和小鼠中（目标1）。我们还将确定糖皮质激素是否通过刺激 通过阻断成骨细胞系细胞凋亡的诱导而导致该细胞类型的凋亡。这将是 通过在该细胞谱系中缺失细胞凋亡所必需的基因（巴克、Bax和胱天蛋白酶8）来完成（Aim 2）。最后，我们将确定糖皮质激素是否通过抑制Wnt信号传导来抑制骨形成， 建立成骨细胞中β-连环蛋白组成性激活的小鼠，并用外源性 糖皮质激素如果我们的假设是正确的，这种方法将防止骨形成的抑制， 糖皮质激素（目标3）。总的来说，拟议的研究将阐明糖皮质激素 过量导致骨质流失，并可能确定新的方法来防止这种骨质流失的患者， 慢性糖皮质激素治疗。