Glucocorticoid-induced Atrophy in Bone and Muscle

糖皮质激素引起的骨和肌肉萎缩

• 批准号: 10301368
• 负责人: Teresita M. Bellido
• 金额: $ 32.44万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301368
• 关键词: Antibodies; Apoptosis; Atrophic; Bone necrosis; Bone remodeling; Bortezomib; Cells; Cholecalciferol; Deterioration; Development; Exhibits; FBXO32 gene; FOXO1A gene; Fall prevention; Fracture; Genetic; Glucocorticoids; Goals; Homeostasis; Hormonal; In Vitro; Incidence; Intervention; Investigation; Jaw; Ligands; Mechanics; Mediating; Mitochondria; Modeling; Mus; Muscle; Muscle Cells; Muscle Contraction; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Musculoskeletal; Musculoskeletal System; Organ Culture Techniques; Osteoblasts; Osteocytes; Osteogenesis; Patients; Pharmacology; Phase; Prevention; Proteasome Inhibition; Receptor Signaling; Regulation; Role; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Skeletal Muscle; TNFSF11 gene; Testing; Therapeutic; Tissues; Up-Regulation; Vitamin D3 Receptor; Work; base; bisphosphonate; bone; bone loss; bone preservation; bone turnover; falls; fracture risk; in vivo; inhibitor/antagonist; mineralization; muscle form; muscle strength; notch protein; novel; novel therapeutic intervention; preservation; prevent; proteostasis; receptor; restoration; standard of care; transcription factor; ubiquitin-protein ligase

Excess of glucocorticoids (GC) has devastating effects on the musculoskeletal system with 30-50% of long-term treated patients exhibiting bone fractures. GC induce bone loss by increasing resorption and decreasing for- mation; and also induce muscle loss and weakness leading to higher incidence of falls. The combined effects on bone and muscle largely account for the increased fracture risk with GC. Inhibition of resorption (the current standard of care) stops bone loss; but, markedly reduces bone turnover resulting in microdamage accumulation with potential development of osteonecrosis of the jaw and atypical fractures; and does not prevent muscle weakness. Therefore, osteoanabolic therapeutic approaches that build new bone and simultaneously interfere with GC actions in muscle are sorely needed. Work leading to this application demonstrates that GC increase the expression of the proteasomal degradation inducers E3 ubiquitin ligases atrogin1, MuRF1, and MUSA1 (atrogenes) in both muscle and bone, a novel finding as atrogenes are traditionally considered muscle-specific. In addition, inhibition of proteasomal degradation with bortezomib prevents GC-induced osteoblast apoptosis and, further, bortezomib or silencing of MuRF1 in osteoblasts prevents GC-induced decrease in matrix mineral- ization in vitro. Moreover, activation of the Vitamin D receptor (VDR) has beneficial musculoskeletal effects and might prevent falls. We found that VDR signaling prevents GC-induced: 1) atrogene expression in bone and muscle ex vivo, 2) the increase in Sost expression ex vivo, and 3) apoptosis of osteoblasts and osteocytes in vitro. Based on these lines of evidence, we hypothesize that atrogene upregulation is a common mechanism underlying GC actions in bone and muscle and that interventions that interfere with atrogene expression or function will prevent GC harmful actions in both tissues. We will test this hypothesis using in vivo, ex vivo, and in vitro approaches. Aim1 will examine whether genetic loss of expression or function of MuRF1 or pharmaco- logic inhibition of the proteasome with bortezomib interfere with atrogene expression/function and counteracts GC-induced bone or muscle atrophy in vivo, in prevention and restoration models; and whether genetic deletion of Notch or FoxO1, or pharmacologic inhibition of Notch signaling prevents muscle atrophy induced by GC. Aim2 will investigate the mechanism of action of VDR signaling on GC-induced bone and muscle atrophy, by examin- ing whether VDR signaling (induced with 1,25-D3 or eldecalcitol/ED-17, a VDR ligand with reduced hypercalce- mic action) counteracts GC regulation of proteostasis, mitochondrial dynamics and cellular energetics in bone and muscle; by studying whether VDR signaling reverses the inhibition of anabolic signaling and the stimulation of catabolic signaling mediated by Sost upregulation induced by GC in bone, in mice with genetic deletion of the VDR in muscle (HSA-MerCreMer) and respective control littermates; and by determining whether VDR signaling prevents GC effects on muscle fiber type composition (glycolytic versus oxidative), and/or preserves Ryn recep- tor-mediated muscle contraction.

过量的糖皮质激素 (GC) 对肌肉骨骼系统具有破坏性影响，30-50% 的长期影响 接受治疗的出现骨折的患者。 GC 通过增加骨吸收和减少骨吸收来诱导骨质流失 化；还会引起肌肉损失和虚弱，导致跌倒发生率更高。综合影响 骨和肌肉在很大程度上是 GC 骨折风险增加的原因。抑制吸收（电流 标准护理）阻止骨质流失；但是，显着降低骨转换，导致微损伤累积 可能发生颌骨坏死和非典型骨折；并且不妨碍肌肉 弱点。因此，骨合成代谢治疗方法可以构建新骨并同时干扰 肌肉中迫切需要 GC 作用。该应用程序的工作表明 GC 增加 蛋白酶体降解诱导剂 E3 泛素连接酶 atrogin1、MuRF1 和 MUSA1 的表达 （atrogenes）存在于肌肉和骨骼中，这是一个新的发现，因为 atrogenes 传统上被认为是肌肉特异性的。 此外，硼替佐米抑制蛋白酶体降解可防止 GC 诱导的成骨细胞凋亡 此外，硼替佐米或成骨细胞中 MuRF1 的沉默可防止 GC 诱导的基质矿物质减少 体外化。此外，维生素 D 受体 (VDR) 的激活具有有益的肌肉骨骼作用， 可能会防止跌倒。我们发现 VDR 信号传导可防止 GC 诱导的：1) 骨中的 atrogene 表达 离体肌肉，2) 离体 Sost 表达增加，3) 成骨细胞和骨细胞凋亡 体外。基于这些证据，我们假设 atrogene 上调是一种常见机制 骨和肌肉中潜在的 GC 作用以及干扰 atrogene 表达或的干预措施 功能将防止 GC 在两个组织中产生有害作用。我们将使用体内、离体和 体外方法。 Aim1 将检查 MuRF1 或药物的表达或功能是否存在遗传缺失。 用硼替佐米对蛋白酶体进行逻辑抑制会干扰 atrogene 表达/功能并产生抵消作用 在预防和恢复模型中，GC 诱导的体内骨或肌肉萎缩；以及是否有基因缺失 Notch 或 FoxO1 的作用，或对 Notch 信号传导的药物抑制可防止 GC 引起的肌肉萎缩。目标2 将研究 VDR 信号传导对 GC 诱导的骨和肌肉萎缩的作用机制，通过检查 是否 VDR 信号传导（用 1,25-D3 或 eldecalcitol/ED-17 诱导，一种具有减少高钙血症的 VDR 配体） mic 作用）抵消 GC 对骨中蛋白质稳态、线粒体动力学和细胞能量学的调节 和肌肉；通过研究 VDR 信号传导是否逆转合成代谢信号传导的抑制和刺激 骨中 GC 诱导的 Sost 上调介导的分解代谢信号在具有 GC 基因缺失的小鼠中 肌肉中的 VDR (HSA-MerCreMer) 和相应的对照同窝小鼠；并通过确定VDR信令是否 防止 GC 对肌纤维类型成分（糖酵解与氧化）的影响，和/或保留 Ryn 受体 Tor 介导的肌肉收缩。