Muscle Regulation of Osteoblast/Osteocyte Function in Young

随着年龄的增长，骨骼的质量会减少，脆性和骨折的易感性会增加，而且 不清楚为什么锻炼会随着年龄的增长而变得不那么有效。骨细胞不仅仅是一种机械感觉细胞 这是对机械负荷的反应，但也是调节破骨细胞和成骨细胞的因素的来源 发挥内分泌细胞的作用，调节其他器官。和骨细胞一样，肌肉也是信号因子的来源， 取名为“肌肉男”。因此，我们假设，活跃的肌肉不仅加载骨骼，而且还发送 对骨细胞，尤其是骨细胞具有有益的协同作用的可溶性信号。我们令人兴奋的数据 显示分化的C2C12肌管的条件培养液(CM)保护骨细胞免受 糖皮质激素的细胞凋亡作用。有趣的是，来自分化的肌管的CM具有更强的抗 未分化成肌细胞的细胞凋亡作用优于CM。我们还发现，Myotube CM增强了 骨细胞对剪切力的反应，包括前列腺素的产生，t&gt；-连环蛋白易位到 细胞核和Akt的磷酸化。这些结果得到了来自分离的完整肌肉的CM的证实 5月龄小鼠比目鱼肌和指长伸肌的外植体，具有相似的保护作用 对骨细胞的抗凋亡作用。与之形成鲜明对比的是，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 与负荷对骨骼的影响无关，在衰老过程中，正向肌肉信号减弱或 转化为与衰老相关的骨细胞功能下降的负面信号。以下是 提出了具体的目标：确定肌肉溶解因子对骨细胞活性的影响和 并确定衰老如何影响肌肉细胞调节骨细胞功能的能力。这个 这些特定目标的完成将极大地推动肌肉骨骼生物学领域的发展。鉴定 年轻肌肉产生的骨细胞活性因子和老年产生的骨细胞凋亡因子 肌肉是新奇的，也是范式的转变。这些肌肉信号转导因子的特征及其对 随着年龄的增长，骨细胞应该会导致治疗骨骼和肌肉丢失的新疗法。 相关性(请参阅说明)： 骨质疏松症和老年性骨质疏松症通常与年龄有关，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质丢失的分子机制。 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 老龄化人口的生活。

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.