Glucocorticoid-induced Atrophy in Bone and Muscle

糖皮质激素引起的骨和肌肉萎缩

• 批准号: 10463792
• 负责人: Teresita M. Bellido
• 金额: $ 33.11万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463792
• 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; antagonist; base; bisphosphonate; bone; bone loss; bone preservation; bone turnover; falls; fracture risk; in vivo; inhibitor; 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的影响，30-50%的长期服用 治疗后出现骨折的患者。糖皮质激素通过增加骨吸收和降低骨密度而导致骨丢失。 还会导致肌肉丧失和虚弱，从而导致更高的跌倒发生率。综合效应对 骨骼和肌肉是GC骨折风险增加的主要原因。抑制吸收(电流 护理标准)阻止骨丢失；但显著降低骨转换，导致微损伤堆积 有可能发展为颌骨坏死和不典型骨折；并且不能阻止肌肉 软弱。因此，构建新骨并同时干扰的骨合成代谢治疗方法 对于GC来说，肌肉中的作用是非常必要的。导致这一应用程序的工作表明，GC增加 蛋白酶体降解诱导因子E3泛素连接酶阿托金1、MuRF1和MUSA1的表达 (萎缩基因)在肌肉和骨骼中都存在，这是一个新的发现，因为萎缩基因传统上被认为是肌肉特有的。 此外，硼替佐米抑制蛋白酶体的降解可阻止GC诱导的成骨细胞凋亡 此外，Bortezomib或沉默成骨细胞中的MuRF1可阻止GC诱导的基质矿物减少。 体外程序化。此外，维生素D受体(VDR)的激活具有有益的肌肉骨骼效应和 可能会防止摔倒。我们发现VDR信号抑制GC诱导的：1)骨骼和骨骼中的阿托品基因表达 2)SOST在体外的表达增加；3)成骨细胞和骨细胞的凋亡 体外培养。根据这些证据，我们假设阿托品基因上调是一种常见的机制。 骨骼和肌肉中潜在的GC作用以及干扰阿托金表达或 功能将防止GC在这两个组织中的有害行为。我们将使用体内、体外和 体外实验方法。AIM1将检测MuRF1或药物-1的表达或功能的遗传缺失- Bortezomib逻辑抑制蛋白酶体干扰阿托品的表达/功能及其拮抗作用 在预防和修复模型中，GC在体内诱导的骨或肌肉萎缩；以及基因缺失 抑制Notch或FoxO1，或药物抑制Notch信号可预防GC引起的肌肉萎缩。AIM2 将通过研究VDR信号在GC诱导的骨和肌肉萎缩中的作用机制。 VDR信号转导(由1，25-D3或去钙化醇/ED-17诱导的VDR配体是否具有降低的高钙- 小鼠动作)抵消GC对骨骼中蛋白质平衡、线粒体动力学和细胞能量学的调节 和肌肉；通过研究VDR信号是否逆转合成代谢信号和刺激的抑制 Gc基因缺失小鼠骨骼中SOST上调介导的分解代谢信号的研究 肌肉中的VDR(HSA-MerCreMer)和相应的对照窝产仔；并通过确定VDR信号是否 防止GC对肌肉纤维类型组成的影响(糖酵解与氧化)，和/或保留Ryn Recep- 托尔介导的肌肉收缩。

项目成果

Role of connexin 43 in the mechanism of action of alendronate: dissociation of anti-apoptotic and proliferative signaling pathways.

• DOI: 10.1016/j.abb.2011.12.022
• 发表时间: 2012-02-15
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Lezcano V;Bellido T;Plotkin LI;Boland R;Morelli S
• 通讯作者: Morelli S

Role of TGF-β in a mouse model of high turnover renal osteodystrophy.

• DOI: 10.1002/jbmr.2120
• 发表时间: 2014
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Liu S;Song W;Boulanger JH;Tang W;Sabbagh Y;Kelley B;Gotschall R;Ryan S;Phillips L;Malley K;Cao X;Xia TH;Zhen G;Cao X;Ling H;Dechow PC;Bellido TM;Ledbetter SR;Schiavi SC
• 通讯作者: Schiavi SC

Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice.

• DOI: 10.1002/jor.22341
• 发表时间: 2013-07
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Bivi, Nicoletta;Pacheco-Costa, Rafael;Brun, Lucas R.;Murphy, Thomas R.;Farlow, Nathan R.;Robling, Alexander G.;Bellido, Teresita;Plotkin, Lilian I.
• 通讯作者: Plotkin, Lilian I.

Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma.

• DOI: 10.1158/0008-5472.can-15-1703
• 发表时间: 2016-03-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Delgado-Calle J;Anderson J;Cregor MD;Hiasa M;Chirgwin JM;Carlesso N;Yoneda T;Mohammad KS;Plotkin LI;Roodman GD;Bellido T
• 通讯作者: Bellido T