Targeting cellular senescence prevents age-related bone loss in mice.
Targeting cellular senescence prevents age-related bone loss in mice.
复制标题
DOI：
10.1038/nm.4385
复制
发表时间：
2017-09
期刊：
影响因子：
82.9
通讯作者：
Khosla S
中科院分区：
文献类型：
--
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
衰老与细胞衰老增加有关，假设这会推动多种合并症的最终发展。在这里，我们通过多种方法研究衰老细胞在年龄相关性骨丢失中的作用。特别是，我们使用了基因（即，编码在衰老细胞中特异性表达的诱导型胱天蛋白酶8的INK-ATTAC“自杀”转基因）或药理学（即，“衰老清除”化合物）是指消除衰老细胞。我们还使用JAK抑制剂（JAKi）抑制衰老细胞的促炎分泌体的产生。在具有确定的骨丢失的老年（20-22个月）小鼠中，与媒介物处理的小鼠相比，衰老细胞中INK-ATTAC半胱天冬酶8的活化或用衰老清除剂或JAKi处理2-4个月导致更高的骨量和强度以及更好的骨微结构。靶向衰老细胞的有益效果是由于与媒介物处理的小鼠相比，具有维持的（骨小梁）或较高的（皮质骨）骨形成的较低的骨吸收。体外研究表明，衰老细胞条件培养基损害成骨细胞矿化和增强破骨细胞祖细胞存活，导致破骨细胞生成增加。总的来说，这些数据确立了衰老细胞在骨丢失中的因果作用，并证明靶向这些细胞对骨具有抗吸收和合成代谢作用。由于消除衰老细胞和/或抑制其促炎分泌蛋白组也可改善心血管功能，增强胰岛素敏感性，并减少虚弱，因此靶向这一基本机制以预防年龄相关性骨丢失不仅是骨质疏松症的新治疗策略，也是多种年龄相关性合并症的新治疗策略。
Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple co-morbidities. Here, we investigate a role for senescent cells in age-related bone loss by multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC “suicide” transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., “senolytic” compounds) means to eliminate senescent cells. We also inhibited the production of the pro-inflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In old (20–22-months) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2–4 months resulted in higher bone mass and strength and better bone microarchitecture compared to vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular bone) or higher (cortical bone) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent cell-conditioned medium impaired osteoblast mineralization and enhanced osteoclast progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. As eliminating senescent cells and/or inhibiting their pro-inflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis but also for multiple age-related co-morbidities.
登录
查看更多内容
影响因子：
158.5
作者：
Lyles, Kenneth W.;Colon-Emeric, Cathleen S.;Boonen, Steven
通讯作者：
Boonen, Steven
DOI：
10.1084/jem.190.12.1741
发表时间：
1999-12-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Arai F;Miyamoto T;Ohneda O;Inada T;Sudo T;Brasel K;Miyata T;Anderson DM;Suda T
通讯作者：
Suda T
影响因子：
7.8
作者：
Nelson G;Wordsworth J;Wang C;Jurk D;Lawless C;Martin-Ruiz C;von Zglinicki T
通讯作者：
von Zglinicki T
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
6.2
作者：
Burge, Russel;Dawson-Hughes, Bess;Tosteson, Anna
通讯作者：
Tosteson, Anna