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Targeting cellular senescence prevents age-related bone loss in mice

衰老 促炎细胞因子 破骨细胞 骨吸收 成骨细胞 骨质疏松症 细胞生物学 祖细胞 内分泌学 医学 生物 内科学 癌症研究 体外 干细胞 炎症 受体 生物化学
作者
Joshua N. Farr,Ming Xu,Megan Weivoda,David G. Monroe,Daniel G. Fraser,Jennifer L Onken,Brittany A Negley,Jad Sfeir,Mikołaj Ogrodnik,Christine Hachfeld,Nathan K. LeBrasseur,Matthew T. Drake,Robert J. Pignolo,Tamar Pirtskhalava,Tamar Tchkonia,Merry Jo Oursler,James L. Kirkland,Sundeep Khosla
出处
期刊:Nature Medicine [Springer Nature]
卷期号:23 (9): 1072-1079 被引量:909
标识
DOI:10.1038/nm.4385
摘要

Genetic or pharmacological depletion of senescent cells or inhibition of their function reduces bone loss in aged mice. Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities1. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells2,3,4) or pharmacological (i.e., 'senolytic' compounds5,6) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi)3,7. In aged (20- to 22-month-old) 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 than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) 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. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function4, enhances insulin sensitivity3, and reduces frailty7, 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 comorbidities.
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