ROLE OF CASPASE-2 IN OSTEOCOLAST APOPTOSIS AGE-EePENDENT OSTEOPOROSIS

CASPASE-2 在破骨细胞凋亡中的作用年龄相关性骨质疏松症

• 批准号: 7233105
• 负责人: BRIAN A. HERMAN
• 金额: $ 26.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233105
• 关键词: Affect; Age; Aging; Animals; Antioxidants; Apoptosis; Biochemical Reaction; Bone Resorption; Calcium/calmodulin-dependent protein kinase; Calmodulin; Caspase; Cessation of life; Data; Disease; Down-Regulation; Elderly; Endopeptidases; Funding; Knockout Mice; Life; Light; Mediating; Mediator of activation protein; Mitochondria; Mus; NADP; Numbers; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Oxidants; Oxidative Stress; Peptide Hydrolases; Phosphotransferases; Play; Rate; Regulation; Role; Skeleton; Testing; Urine; Wild Type Mouse; base; bone; bone loss; caspase-2; in vivo; oxidation; prevent; pro-caspase-2

Bone is a living organ that is maintained through continuous formation of new bone by osteoblasts and resorption of exiting bone by osteoclasts. Loss of bone mass at advanced ages causes osteoporosis. Caspase-2 is a protease that is involved in programmed cell death (apoptosis). During the last funding period, we found that caspase-2 is an important regulator of bone mass in aging animals. Our critical observation was that aging-associated bone loss in old (24-26 month) caspase-2 null mice was more severe than that in the same age wild type mice. The objective of this proposal is to further study the role of caspase-2 in aging skeleton. Our hypothesis is that caspase-2 mediates mitochondrial-dependent apoptosis of aging osteoclasts, which is induced by oxidative stress in vivo. Lack of caspase-2 activity results in reduced apoptosis of aging osteoclasts, leading to increased bone resorption. To test this hypothesis, first, we will compare the rate of bone formation and bone resorption in old caspase-2 null and wild type mice to show that caspase-2 affects bone resorption. Next, we will compare the apoptosis rate in aging osteoclasts that have increased/decreased antioxidant capacity to show that oxidative stress is a cause of spontaneous apoptosis of aging osteoclasts. Then, we will compare the apoptosis rate of caspase-2 (-/-)and (+/+) aging osteoclasts to show that caspase-2 plays an important role in the spontaneous apoptosis of aging osteoclasts. Finally, we will compare the apoptosis rate in aging osteoclasts that have both altered antioxidant activity and caspase-2 activity to show that caspase-2 is a mediator of oxidative stress-induced apoptosis. Calmodulin (CaM) dependent kinase II (CaMK II) can phosphorylate procaspase-2 and prevent its activation. NADPH, which provides reducing equivalent for various biochemical reactions to scavenge oxidants, also inhibits the activation of procaspase-2 by enhancing CaMK II function. Based on these findings, we will test the hypothesis that oxidative stress activates caspase-2 in aging osteoclasts through down-regulation of NADPH/CaMK II activity by examining the level of NAPDH and oxidation of CaM and CaMK II. Osteoporosis is a serious disease that affects the elderly. The main strategy and mechanism of action of current anti-osteoporosis therapy is to induce osteoclast apoptosis. Therefore, this study will shed the light on the mechanism of apoptosis in osteoclasts and open new avenues for new anti-osteoporosis therapies.

骨骼是一种生物器官，通过成骨细胞连续形成新的骨骼来维持生命器官 通过破骨细胞吸收退出的骨骼。晚期骨骼量的损失会导致骨质疏松症。 caspase-2是一种参与程序性细胞死亡（细胞凋亡）的蛋白酶。在上次资金中 时期，我们发现caspase-2是衰老动物中骨骼质量的重要调节剂。我们的批评 观察到旧（24-26个月）caspase-2无效小鼠的衰老相关的骨质流失更为严重 在同一年龄野生型小鼠中。该提议的目的是进一步研究 老化骨骼中的caspase-2。我们的假设是caspase-2介导线粒体依赖性凋亡 衰老的破骨细胞，由体内氧化应激诱导。缺乏caspase-2活性导致 衰老破骨细胞的凋亡减少，导致骨吸收增加。首先要检验这一假设 我们将比较旧caspase-2 null和野生型小鼠的骨形成和骨吸收速率 表明caspase-2会影响骨吸收。接下来，我们将比较破骨细胞衰老的凋亡率 抗氧化能力增加/降低，表明氧化应激是自发的原因 衰老破骨细胞的凋亡。然后，我们将比较caspase-2（ - / - ）和（+/+）老化的凋亡率 破骨细胞表明caspase-2在衰老的自发凋亡中起重要作用 破骨细胞。最后，我们将比较均改变的破骨细胞的凋亡率 抗氧化活性和caspase-2活性表明caspase-2是氧化应激诱导的中介体 凋亡。钙调蛋白（CAM）依赖性激酶II（CAMK II）可以磷酸化procaspase-2并防止 它的激活。 NADPH，可为各种生化反应提供降低的等效物 氧化剂，还通过增强CAMK II功能抑制procaspase-2的激活。基于这些 调查结果，我们将检验以下假设：氧化应激通过衰老的破骨细胞激活caspase-2 通过检查NAPDH的水平和CAM的氧化水平，对NADPH/CAMK II活性的下调 CAMK II。骨质疏松症是一种严重的疾病，会影响老年人。主要策略和机制 当前的抗骨质疏松疗法的作用是诱导骨细胞凋亡。因此，这项研究将脱落 关于破骨细胞凋亡机制的光和新抗骨质疏松症的新途径 疗法。