Tilton Maryam, Weivoda Megan, Astudillo Potes Maria, Gingery Anne, Liu Alan Y, Tchkonia Tamara, Lu Lichun, Kirkland James L
Walker Department of Mechanical Engineering, The University of Texas at Austin, Austin, Texas, USA.
Department of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Aging Cell. 2024 Dec;23(12):e14421. doi: 10.1111/acel.14421. Epub 2024 Nov 24.
Senescent osteocytes are key contributors to age-related bone loss and fragility; however, the impact of mechanobiological changes in these cells remains poorly understood. This study provides a novel analysis of these changes in primary osteocytes following irradiation-induced senescence. By integrating subcellular mechanical measurements with gene expression analyses, we identified significant, time-dependent alterations in the mechanical properties of senescent bone cells. Increases in classical markers such as SA-β-Gal activity and p16 expression levels confirmed the senescence status post-irradiation. Our key findings include a time-dependent increase in cytoskeletal Young's modulus and altered viscoelastic properties of the plasma membrane, affecting the contractility of primary osteocytes. Additionally, we observed a significant increase in Sclerostin (Sost) expression 21 days post-irradiation. These biophysical changes may impair osteocyte mechanosensation and mechanotransduction, contributing to bone fragility. This is the first study to time-map senescence-associated mechanical changes in the osteocyte cytoskeleton. Our findings highlight the potential of biophysical markers as indicators of cellular senescence, providing more specificity than traditional, variable biomolecular markers. We believe these results may support biomechanical stimulation as a potential therapeutic strategy to rejuvenate aging osteocytes and enhance bone health.
衰老的骨细胞是与年龄相关的骨质流失和骨脆性的关键促成因素；然而，这些细胞中机械生物学变化的影响仍知之甚少。本研究对辐射诱导衰老后的原代骨细胞中的这些变化进行了新颖的分析。通过将亚细胞力学测量与基因表达分析相结合，我们确定了衰老骨细胞力学特性中显著的、随时间变化的改变。衰老相关β-半乳糖苷酶（SA-β-Gal）活性和p16表达水平等经典标志物的增加证实了辐射后的衰老状态。我们的主要发现包括细胞骨架杨氏模量随时间增加以及质膜粘弹性改变，影响原代骨细胞的收缩性。此外，我们观察到辐射后21天硬化蛋白（Sost）表达显著增加。这些生物物理变化可能损害骨细胞的机械感受和机械转导，导致骨脆性增加。这是第一项对骨细胞细胞骨架中与衰老相关的机械变化进行时间映射的研究。我们的发现突出了生物物理标志物作为细胞衰老指标的潜力，比传统的、可变的生物分子标志物具有更高的特异性。我们相信这些结果可能支持生物力学刺激作为一种潜在的治疗策略，以使衰老的骨细胞恢复活力并增强骨骼健康。
