衰老会导致对机械刺激的合成代谢反应降低以及骨量和结构完整性的损失。阿霉素等化疗药物会加剧衰老骨骼的退化，并进一步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。基于先前的研究结果，i) Yoda1（Piezo1 激动剂）促进年轻成年小鼠的骨骼生长并抑制老年小鼠的骨吸收标志物，以及 ii) 适度的胫骨负荷可保护骨骼免受乳腺癌引起的骨质溶解，我们假设将 Yoda1 和适度的负荷可以改善成人和老年骨骼的体内结构完整性，并保护骨骼在化疗后免于恶化。我们首先检查了 4 周 Yoda1（剂量 5mg/kg，5 次/周）和中等胫骨负荷（4.5N 峰值负荷，4Hz，300 个循环，5 天/周）对成熟小鼠的影响。小鼠（约 50 周龄）。研究发现，与单独干预相比，Yoda1 和负荷相结合可以更好地减轻与年龄相关的皮质骨和小梁骨丢失。正如预期的那样，未经治疗的对照组在 4 周内经历了皮质极惯性矩 (Ct.pMOI) 平均下降 -4.3%，并且大多数 (64%) 样本中发生了骨质恶化。相对于未处理，单独加载、单独 Yoda1 以及 Yoda1 和加载组合使 Ct.pMOI 增加了 7.3%、9.5%、12.0%，并使 Ct.pMOI 变化呈阳性的样品百分比增加了 32%、26% 和 43 %，表明联合治疗对衰老相关的骨质流失具有额外的保护作用。我们进一步测试了在成熟小鼠中以 2.5 或 5mg/kg 剂量注射阿霉素两周（六次注射）后治疗效果是否得以保留。正如预期的那样，阿霉素增加了骨细胞凋亡，改变了骨重塑，并损害了骨结构。然而，DOX 诱导的效果太严重，无法通过单独或组合的 Yoda1 和加载来挽救，尽管单独或组合加载和 Yoda1 使表现出阳性反应的小鼠数量相对增加了 0%、15% 和 29%暴露于阿霉素后不进行干预。总体而言，这项研究支持了基于 Yoda1 的策略在减轻衰老和阿霉素引起的有害骨骼影响方面的潜力和挑战。版权所有 © 2024。由 Elsevier Inc. 出版。

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.Copyright © 2024. Published by Elsevier Inc.