Muscle Regulation of Osteoblast/Osteocyte Function in Young

年轻人成骨细胞/骨细胞功能的肌肉调节

• 批准号: 8281061
• 负责人: Lynda F Bonewald
• 金额: $ 32.05万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281061
• 关键词: Adult; Affect; Age; Aging; Apoptosis; Apoptotic; Area; Autophagocytosis; Biology; Bone Matrix; Bone Surface; Bone remodeling; Cell Culture Techniques; Cell Death; Cell Nucleus; Cell physiology; Cells; Cessation of life; Communication; Conditioned Culture Media; Data; Development; Disease; Employee Strikes; Endocrine; Endocrine Glands; Exercise; FGF21 gene; Follistatin; Fracture; Glucocorticoids; Goals; Growth and Development function; Homeostasis; In Vitro; Instruction; Insulin; Lead; Left; Liquid substance; Mechanics; Minerals; Modeling; Molecular; Morphology; Mus; Muscle; Muscle Cells; Muscle Fibers; Musculoskeletal; Myoblasts; Necrosis; Organ; Osteoblasts; Osteoclasts; Osteocytes; Osteoid; Osteoporosis; Phosphorylation; Play; Predisposition; Process; Prostaglandin Production; Public Health; Quality of life; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeleton; Somatotropin; Source; Staging; Stress; Testing; The Sun; Undifferentiated; United States; age related; aged; aging population; bone; bone cell; bone mass; calcium phosphate; cell type; effective therapy; extensor digitorum; leukemia inhibitory factor; mineralization; muscle aging; novel; novel therapeutics; progenitor; programs; response; sarcopenia; shear stress

With aging, the skeleton decreases In mass and Increases In fragility and susceptibility to fracture and it is not clear why exercise becomes less effective with aging.The osteocyte is not only a mechanosensory cell that responds to mechanical load, but also a source of factors that regulate osteoclasts and osteoblasts and act as endocrine cells to regulate other organs. Like osteocytes, muscle is also a source of signaling factors, tenned 'myokines'. Therefore, we hypothesize that active muscle not only loads the bone, but also sends soluble signals that have beneficial synergistic effects on bone cells, especially osteocytes. Our exciting data show that conditioned media (CM) from differentiated C2C12 myotubes protects osteocytes from the apoptotic effects of glucocorticoid. Interestingly, CM from differentiated myotubes had a more potent anti- apoptotic effect than CM from undifferentiated myoblasts. We have also found that myotube CM enhances osteocyte responses to shear stress, including prostaglandin production, t>-catenin translocation to the nucleus, and Akt phosphorylation. These results were confirmed using CM from isolated whole muscle explants of soleus and extensor digitomm longus muscle from 5 month old mice, which had similar protective anti-apoptotic effects on osteocytes. In striking contrast, muscle explant CM from aged 22 month old mice actually induced osteocyte cell death. Our overall hypothesis is that muscle can signal bone cells independent ofthe effect of loading on the skeleton and during aging, positive muscle signaling declines or converts to negative signals contributing to the aging-related decline in bone cell function. The following specific aims are proposed: To determine the effects of muscle soluble Actors on osteocyte viability and function and to determine how aging affects the ability of muscle cells to regulate osteocyte function. The completion of these specific aims will significantiy advance the field of musculoskeletal biology. Identification of osteocyte viability factors produced by young muscle and of osteocyte apoptotic factors produced by aged muscle is novel and paradigm shifting. Characterizing these muscle signaling factors and their effects on bone cells should lead to novel therapeutics for treatment of both bone and muscle loss with age. RELEVANCE (See instructions): Osteoporosis and aging sarcopenia, usually occur concun-entiy with age and is a major public health problem in the United States. Our goal is to Identify molecular mechanisms that contribute to loss of bone mass with aging, which will allow the development of effective treatments and the improvement in quality of life for the aging population.

随着年龄的增长，骨骼的质量减少，脆弱性和骨折的敏感性增加， 目前尚不清楚为什么随着年龄的增长，锻炼的效果越来越差。骨细胞不仅是一种机械感觉细胞， 它对机械负荷有反应，但也是调节破骨细胞和成骨细胞的因子的来源， 作为内分泌细胞调节其他器官。像骨细胞一样，肌肉也是信号因子的来源， 称为“肌动素”。因此，我们假设活跃的肌肉不仅负荷骨骼，而且还发送 可溶性信号对骨细胞，尤其是骨细胞具有有益的协同作用。我们令人兴奋的数据 显示来自分化的C2 C12肌管的条件培养基（CM）保护骨细胞免受 糖皮质激素的凋亡作用。有趣的是，来自分化肌管的CM具有更强的抗- 与未分化成肌细胞的CM相比，我们还发现，肌管CM增强 骨细胞对剪切应力的反应，包括前列腺素的产生，t>-连环蛋白向骨细胞的转位， 细胞核和Akt磷酸化。这些结果用来自分离的全肌肉的CM证实 5月龄小鼠比目鱼肌和趾长伸肌组织块， 对骨细胞的抗凋亡作用。与此形成鲜明对比的是，来自22月龄小鼠的肌肉外植体CM 实际上导致了骨细胞的死亡。我们的总体假设是肌肉可以向骨细胞发出信号 独立于骨骼上的负荷的影响，在衰老过程中，正肌肉信号下降，或 转化为负信号，导致骨细胞功能的老化相关下降。以下 提出了具体的目标：确定肌肉可溶性因子对骨细胞活力的影响， 功能，并确定衰老如何影响肌肉细胞调节骨细胞功能的能力。的 这些具体目标的完成将显著地推进肌肉骨骼生物学领域。识别 年轻肌肉产生的骨细胞活力因子和老年肌肉产生的骨细胞凋亡因子 muscle肌肉is novel新颖and paradigm范式transforming转移.表征这些肌肉信号传导因子及其对 骨细胞应该导致治疗骨和肌肉随年龄的损失的新疗法。 相关性（参见说明）： 骨质疏松症和老年性肌肉减少症常随年龄增长而发生，是一种主要的公共卫生问题 在美国的问题。我们的目标是确定导致骨丢失的分子机制 随着年龄的增长，这将使有效的治疗方法的发展和质量的提高， 老年人的生活。