Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy
Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy
复制标题
雷帕霉素通过激活骨细胞自噬降低老年骨质疏松症的严重程度
DOI：
10.1007/s00198-015-3325-5
复制
发表时间：
2016-03-01
影响因子：
4
通讯作者：
Lin, D.
中科院分区：
文献类型：
--
作者：
Luo, D.;Ren, H.;Lin, D.
骨细胞是骨重塑的协调者，骨细胞自噬功能下降参与了老年性骨质疏松症的发生。我们的研究结果表明，雷帕霉素，至少部分通过激活骨细胞自噬，降低老年雄性大鼠骨小梁中与年龄相关的骨变化的严重程度。IntroductionPrevious文献表明，骨细胞是骨重塑的协调者，与年龄相关的骨细胞数量下降与老年性骨质疏松症有关。自噬是维持骨细胞活力的重要细胞保护机制，随着年龄的增长，骨细胞自噬功能的丧失与老年性骨质疏松症有关。本研究旨在探讨自噬激活剂雷帕霉素（rapamycin）是否通过诱导骨细胞自噬对老年性骨质疏松症具有保护作用。腹膜内施用雷帕霉素（lmg/kg重量/天）或DMSO媒介物对照12周。用Micro-CT测定骨密度和骨微结构。对骨进行荧光染料标记以测量矿物质沉积率（MAR）。TRAP染色评价破骨细胞数量。还分析了骨转换标志物的血浆水平。雷帕霉素对骨细胞自噬的影响通过免疫组织化学、Western印迹和q-PCR来确定。TUNEL法被用来确定骨细胞凋亡的患病率。ResultsMicro-CT评估表明，雷帕霉素对年龄相关的骨小梁骨丢失有保护作用。与对照组相比，雷帕霉素组MAR明显增加，破骨细胞数量明显减少。此外，雷帕霉素还诱导骨细胞自噬，表现为LC 3阳性骨细胞增加和LC 3周转增加。此外，用雷帕霉素治疗的大鼠表现出减少凋亡的骨细胞测定TUNEL.ConclusionsThese结果表明，雷帕霉素，至少部分通过激活骨细胞自噬，降低了老年雄性大鼠骨小梁的年龄相关的骨变化的严重程度。因此，雷帕霉素可能是治疗老年性骨质疏松症的一种可行的方法。
SummaryOsteocyte is the orchestrator of bone remolding and decline in osteocyte autophagy is involved in senile osteoporosis. Our results suggested that rapamycin, at least in part by activating osteocyte autophagy, reduced the severity of age-related bone changes in trabecular bone of old male rats.IntroductionPrevious literatures have showed that osteocyte is the orchestrator of bone remolding and age-related decline in osteocyte number is associated with senile osteoporosis. Autophagy is an important cellular protective mechanism which can preserve osteocyte viability and failure of autophagy in osteocyte with age has been linked to senile osteoporosis. The purpose of this study was to explore whether rapamycin, one activator of autophagy, has protective effects on senile osteoporosis through inducing osteocyte autophagy.MethodsFifty-two 24-month-old male Sprague-Dawley (SD) rats were randomly divided into two groups. Rapamycin (1 mg/kg weight/day) or DMSO vehicle control was administered intraperitoneally for 12 weeks. BMD and bone microstructure were determined by Micro-CT. Fluorochrome labeling of the bones was performed to measure the mineral apposition rate (MAR). TRAP staining was performed to evaluate osteoclast number. The plasma levels of bone turnover markers were also analyzed. The effects of rapamycin on osteocyte autophagy were determined by immunohistochemistry, Western blot, and q-PCR. TUNEL was used to determine the prevalence of osteocyte apoptosis.ResultsMicro-CT evaluation demonstrated that rapamycin had a protective effect on age-related bone loss in trabecular bone. Besides, rapamycin resulted in an obvious increase of MAR and a decrease of osteoclast number in contrast to the control group. Furthermore, rapamycin also induced autophagy in osteocyte demonstrated by increased LC3-positive osteocyte and increased LC3 turnover. In addition, rats treated with rapamycin exhibited decreased apoptosis of osteocyte determined by TUNEL.ConclusionsThese results suggested that rapamycin, at least in part by activating osteocyte autophagy, reduced the severity of age-related bone changes in trabecular bone of old male rats. Therefore, rapamycin might be a feasible therapeutic approach for senile osteoporosis.