Glucocorticoid-induced Atrophy in Bone and Muscle

糖皮质激素引起的骨和肌肉萎缩

• 批准号: 10225876
• 负责人: Teresita M. Bellido
• 金额: $ 22.59万
• 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/10225876
• 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）对肌肉骨骼系统有破坏性影响，30-50%的长期 治疗骨折的患者。GC通过增加骨吸收和减少骨吸收来诱导骨丢失。 并且还诱发肌肉损失和无力，导致更高的福尔斯发生率。综合影响 骨骼和肌肉在很大程度上导致GC骨折风险增加。抑制再吸收（电流 标准治疗）阻止骨丢失;但显著降低骨转换，导致微损伤累积 有可能发生颌骨骨坏死和非典型骨折;并且不会阻止肌肉 弱点因此，骨合成代谢治疗方法，建立新的骨，同时干扰 肌肉中的GC作用是非常需要的。导致此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atrogin 1、MuRF 1和MUSA 1的表达 这是一项新的发现，因为传统上认为萎缩基因是肌肉特异性的。 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，硼替佐米或沉默成骨细胞中的MuRF 1可防止GC诱导的基质矿物质减少， 体外诱导。此外，维生素D受体（VDR）的激活具有有益的肌肉骨骼效应， 可以防止福尔斯。我们发现VDR信号传导阻止GC诱导的：1）骨中的atrogene表达， 肌肉离体，2）Sost表达的增加离体，和3）成骨细胞和骨细胞的凋亡， 体外基于这些证据，我们假设抑癌基因上调是一种常见的机制 骨和肌肉中潜在的GC作用，以及干扰atrogene表达或 功能将防止GC在两种组织中的有害作用。我们将使用体内、离体和 in vitro体外approaches方法. Aim 1将检查MuRF 1或药理学基因的表达或功能的遗传缺失是否会导致MuRF 1或药理学基因的缺失。 硼替佐米对蛋白酶体的逻辑抑制干扰了抑癌基因的表达/功能， GC诱导的骨或肌肉萎缩在体内，在预防和恢复模型;以及是否遗传缺失 Notch或FoxO 1的抑制或Notch信号传导的药理学抑制可防止GC诱导的肌肉萎缩。AIM2 将通过检查来研究VDR信号对GC诱导的骨和肌肉萎缩的作用机制- 研究VDR信号传导（用1，25-D3或艾地骨化醇/艾德-17诱导， 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 通过研究VDR信号是否逆转合成代谢信号的抑制和刺激， 在骨中GC诱导的Sost上调介导的分解代谢信号传导中， 肌肉中的VDR（HSA-MerCreMer）和相应的对照同窝仔;以及通过确定VDR信号传导是否 防止GC对肌纤维类型组成的影响（糖酵解对氧化），和/或保留瑞恩受体， TOR介导的肌肉收缩。