通过基于机械生物学的疗法缓解成熟小鼠的衰老和多柔比星诱导的骨质流失。

IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Bone Pub Date : 2024-08-13 DOI:10.1016/j.bone.2024.117235
Murtaza Wasi , Tiankuo Chu , Rosa M. Guerra , Rory Kooker , Kenneth Maldonado , Xuehua Li , Chun-Yu Lin , Xin Song , Jinhu Xiong , Lidan You , Liyun Wang
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引用次数: 0

摘要

衰老会导致对机械刺激的合成代谢反应减弱,骨质和结构完整性丧失。多柔比星等化疗药物会加剧衰老骨骼的退化,使老年癌症患者面临更高的骨折风险。为了缓解这一临床问题,我们提出并测试了一种基于机械生物学的新型疗法。基于之前的研究结果(i)Piezo1 激动剂 Yoda1 促进了年轻成年小鼠的骨生长并抑制了老年小鼠的骨吸收标记物;(ii)适度的胫骨负荷保护了骨骼免受乳腺癌诱导的骨溶解的影响),我们假设 Yoda1 和适度负荷相结合将改善体内成年和老年骨骼的结构完整性并保护骨骼免受化疗后的退化。我们首先对成年小鼠(约 50 周龄)进行了为期 4 周的 Yoda1(剂量为 5 毫克/千克,5 次/周)和适度胫骨负荷(峰值负荷为 4.5 牛,4 赫兹,300 个周期,5 天/周)的单独或联合试验。研究发现,Yoda1和加载相结合比单独干预能更好地缓解年龄相关的皮质和骨小梁骨质流失。不出所料,未接受治疗的对照组在四周内皮质极惯性矩(Ct.pMOI)平均下降了-4.3%,大多数样本(64%)的骨质都出现了退化。与不治疗相比,单独加载、单独Yoda1以及Yoda1和加载联合疗法可使Ct.pMOI分别增加7.3%、9.5%和12.0%,并使Ct.pMOI发生正向变化的样本比例分别增加32%、26%和43%,这表明联合疗法对衰老相关的骨质流失具有叠加保护作用。我们进一步测试了成熟小鼠在接受 2.5 或 5 毫克/千克剂量的多柔比星治疗两周(注射六次)后是否能保持疗效。不出所料,多柔比星会增加骨细胞凋亡、改变骨重塑和损害骨结构。然而,DOX诱导的影响过于严重,Yoda1和负载(单独或联合使用)都无法挽救,尽管负载和Yoda1单独或联合使用,相对于暴露于多柔比星后未进行干预,显示阳性反应的小鼠数量分别增加了0%、+15%和+29%。总之,这项研究证实了基于 Yoda1 的策略在减轻衰老和多柔比星对骨骼造成的有害影响方面的潜力和挑战。
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Mitigating aging and doxorubicin induced bone loss in mature mice via mechanobiology based treatments

Aging leads to a reduced anabolic response to mechanical stimuli and a loss of bone mass and structural integrity. Chemotherapy agents such as doxorubicin exacerbate the degeneration of aging skeleton and further subject older cancer patients to a higher fracture risk. To alleviate this clinical problem, we proposed and tested a novel mechanobiology-based therapy. Building upon prior findings that i) Yoda1, the Piezo1 agonist, promoted bone growth in young adult mice and suppressed bone resorption markers in aged mice, and ii) moderate tibial loading protected bone from breast cancer-induced osteolysis, we hypothesized that combined Yoda1 and moderate loading would improve the structural integrity of adult and aged skeletons in vivo and protect bones from deterioration after chemotherapy. We first examined the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles for 5 days/week), individually and combined, on mature mice (∼50 weeks of age). Combined Yoda1 and loading was found to mitigate age-associated cortical and trabecular bone loss better than individual interventions. As expected, the non-treated controls experienced an average drop of cortical polar moment of inertia (Ct.pMOI) by −4.3 % over four weeks and the bone deterioration occurred in the majority (64 %) of the samples. Relative to no treatment, loading alone, Yoda1 alone, and combined Yoda1 and loading increased Ct.pMOI by +7.3 %, +9.5 %, +12.0 % and increased the % of samples with positive Ct.pMOI changes by +32 %, +26 %, and +43 %, respectively, suggesting an additive protection of aging-related bone loss for the combined therapy. We further tested if the treatment efficacy was preserved in mature mice following two weeks (six injections) of doxorubicin at the dose of 2.5 or 5 mg/kg. As expected, doxorubicin increased osteocyte apoptosis, altered bone remodeling, and impaired bone structure. However, the effects induced by DOX were too severe to be rescued by Yoda1 and loading, alone or combined, although loading and Yoda1 individually, or combined, increased the number of mice showing positive responsiveness by 0 %, +15 %, and +29 % relative to no intervention after doxorubicin exposure. Overall, this study supported the potentials and challenges of the Yoda1-based strategy in mitigating the detrimental skeletal effects caused by aging and doxorubicin.

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来源期刊
Bone
Bone 医学-内分泌学与代谢
CiteScore
8.90
自引率
4.90%
发文量
264
审稿时长
30 days
期刊介绍: BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism. The Journal also encourages submissions related to interactions of bone with other organ systems, including cartilage, endocrine, muscle, fat, neural, vascular, gastrointestinal, hematopoietic, and immune systems. Particular attention is placed on the application of experimental studies to clinical practice.
期刊最新文献
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