Tilton Maryam, Liao Junhan, Kim Chanul, Shaygani Hossein, Potes Maria Astudillo, Cordova Domenic, Kirkland James L, Miller Kyle M
Walker Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX, USA.
Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
bioRxiv. 2025 Jan 26:2024.09.28.615585. doi: 10.1101/2024.09.28.615585.
Aging-related bone loss significantly impacts the growing elderly population globally, leading to debilitating conditions such as osteoporosis. Senescent osteocytes play a crucial role in the aging process of bone. This longitudinal study examines the impact of continuous local and paracrine exposure to senescence-associated secretory phenotype (SASP) factors on senescence-associated biophysical and biomolecular markers in osteocytes. We found significant cytoskeletal stiffening in irradiated osteocytes, accompanied by expansion of F-actin areas and a decline in dendritic integrity. These changes, correlating with alterations in pro-inflammatory cytokine levels and osteocyte-specific gene expression, support the reliability of biophysical markers for identifying senescent osteocytes. Notably, local accumulation of SASP factors had a more pronounced impact on osteocyte properties than paracrine effects, suggesting that the interplay between local and paracrine exposure could substantially influence cellular aging. This study underscores the importance of osteocyte mechanical and morphological properties as biophysical markers of senescence, highlighting their time-dependence and differential effects of local and paracrine SASP exposure. Collectively, our investigation into biophysical senescence markers offer unique and reliable functional hallmarks for non-invasive identification of senescent osteocytes, providing insights that could inform therapeutic strategies to mitigate aging-related bone loss.
与衰老相关的骨质流失对全球不断增长的老年人口产生了重大影响，导致了骨质疏松症等使人衰弱的疾病。衰老的骨细胞在骨骼衰老过程中起着至关重要的作用。这项纵向研究考察了持续局部和旁分泌暴露于衰老相关分泌表型（SASP）因子对骨细胞中衰老相关生物物理和生物分子标志物的影响。我们发现，受辐照的骨细胞出现了明显的细胞骨架硬化，同时伴有F-肌动蛋白区域的扩大和树突完整性的下降。这些变化与促炎细胞因子水平和骨细胞特异性基因表达的改变相关，支持了生物物理标志物在识别衰老骨细胞方面的可靠性。值得注意的是，SASP因子的局部积累对骨细胞特性的影响比旁分泌效应更为显著，这表明局部和旁分泌暴露之间的相互作用可能会极大地影响细胞衰老。这项研究强调了骨细胞的机械和形态特性作为衰老生物物理标志物的重要性，突出了它们的时间依赖性以及局部和旁分泌SASP暴露的不同影响。总体而言，我们对生物物理衰老标志物的研究为非侵入性识别衰老骨细胞提供了独特而可靠的功能特征，为减轻与衰老相关的骨质流失的治疗策略提供了参考依据。
