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.

糖皮质激素过多（GC）对长期30-50％的肌肉骨骼系统具有毁灭性影响 治疗的患者表现出骨折。 GC通过增加吸收并减少for-诱导骨质流失。 ;并引起肌肉丧失和无力，导致跌倒的发病率更高。对 骨骼和肌肉在很大程度上说明了GC的骨折风险增加。抑制吸收（电流 护理标准）停止骨质流失；但是，明显减少了骨转换，导致微塑料积累 随着颌骨和非典型裂缝的骨质分泌的潜在发展；并且不能防止肌肉 弱点。因此，骨代谢的治疗方法可以构建新的骨头并同时干扰 迫切需要使用GC动作。导致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 （肌根）在肌肉和骨骼中，作为催化剂的一种新颖发现在传统上被认为是肌肉特异性的。 另外，用硼替佐米抑制蛋白酶体降解可防止GC诱导的成骨细胞细胞凋亡 此外，成骨细胞中Murf1的硼替佐米或沉默可防止GC诱导的基质矿物质的降低 体外。此外，维生素D受体（VDR）的激活具有有益的肌肉骨骼作用，并且 可能会防止跌倒。我们发现VDR信号传导阻止了GC引起的：1） 肌肉离体，2）sost表达的增加，3）成骨细胞和骨细胞的细胞凋亡 体外。基于这些证据，我们假设阳性上调是一种常见的机制 骨骼和肌肉中的GC基础作用以及干扰贫民表达或的干预措施 功能将防止两种组织中的GC有害作用。我们将使用体内，Ex Vivo和 体外方法。 AIM1将检查MURF1或Pharmaco-的遗传丧失表达或功能是否 bortezomib对蛋白酶体的逻辑抑制会干扰阳性蛋白表达/功能和应对 GC诱导的骨或肌肉萎缩在体内，预防和恢复模型；以及遗传缺失是否 Notch或FOXO1的凹入或对Notch信号的药理抑制可防止GC诱导的肌肉萎缩。 AIM2 通过检查，将研究VDR信号传导对GC诱导的骨骼和肌肉萎缩的作用机理。 VDR信号传导（用1,25-D3诱导还是Eldecalcitol/Ed-17，一种VDR配体，具有降低的高电量 - 麦克风作用）抵消骨骼中蛋白质量，线粒体动力学和细胞能量的GC调节 和肌肉；通过研究VDR信号是否逆转合成代谢信号的抑制和刺激 由GC在骨骼中诱导的SOST上调介导的分解代谢信号传导，在遗传缺失的小鼠中 肌肉中的VDR（HSA-Mercremer）和各自的控制同窝仔；并通过确定VDR是否信号 防止GC对肌肉纤维类型组成（糖酵解与氧化）的影响，并保存Ryn Recep- Tor介导的肌肉收缩。