Glucocorticoid-induced Atrophy in Bone and Muscle

糖皮质激素引起的骨和肌肉萎缩

基本信息

  • 批准号:
    10225876
  • 负责人:
  • 金额:
    $ 22.59万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,其长期影响为30-50%

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Teresita M. Bellido其他文献

The development of a collagen-nanoscale hydroxyapatite three-dimensional (3D) emin vitro/em culture system for reproducing osteocyte differentiation and tissue mineralization
用于复制骨细胞分化和组织矿化的胶原蛋白-纳米羟基磷灰石三维(3D)体外培养系统的开发
  • DOI:
    10.1016/j.biomaterials.2025.123451
  • 发表时间:
    2026-01-01
  • 期刊:
  • 影响因子:
    12.900
  • 作者:
    Xiaoyu Xu;Brian T. Golz;Brennan T. Flannery;Maxime A. Gallant;Whitney A. Bullock;Teresita M. Bellido;Eric A. Nauman;Sherry L. Voytik-Harbin;Dianne Little;Russell P. Main
  • 通讯作者:
    Russell P. Main
Allogeneic Mesenchymal Stromal Cells Increase In Vivo Muscle Function and Promote Muscle Fiber Regeneration in a Diabetic Mouse Model of Critical Limb-Threatening Ischemia
  • DOI:
    10.1016/j.jvs.2020.06.057
  • 发表时间:
    2020-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Justin R. King;Katherin E. Leckie;Amy Y. Sato;Teresita M. Bellido;Marlee Yancey;Leni Moldovan;Michael P. Murphy;Steven J. Miller
  • 通讯作者:
    Steven J. Miller

Teresita M. Bellido的其他文献

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{{ truncateString('Teresita M. Bellido', 18)}}的其他基金

ASBMR Three Year Pre-Meeting Symposia
ASBMR 三年会前研讨会
  • 批准号:
    10468525
  • 财政年份:
    2022
  • 资助金额:
    $ 22.59万
  • 项目类别:
ASBMR Three Year Pre-Meeting Symposia
ASBMR 三年会前研讨会
  • 批准号:
    10625441
  • 财政年份:
    2022
  • 资助金额:
    $ 22.59万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 22.59万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 22.59万
  • 项目类别:
BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD
BLR
  • 批准号:
    9911968
  • 财政年份:
    2019
  • 资助金额:
    $ 22.59万
  • 项目类别:
BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD
BLR
  • 批准号:
    10618285
  • 财政年份:
    2019
  • 资助金额:
    $ 22.59万
  • 项目类别:
BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD
BLR
  • 批准号:
    10265416
  • 财政年份:
    2019
  • 资助金额:
    $ 22.59万
  • 项目类别:
BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD
BLR
  • 批准号:
    10328422
  • 财政年份:
    2019
  • 资助金额:
    $ 22.59万
  • 项目类别:
BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD
BLR
  • 批准号:
    9764747
  • 财政年份:
    2019
  • 资助金额:
    $ 22.59万
  • 项目类别:
BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD
BLR
  • 批准号:
    10454217
  • 财政年份:
    2019
  • 资助金额:
    $ 22.59万
  • 项目类别:

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