Lu Jinsen, Rao Srinivasa Rao, Knowles Helen, Zhan Haoqun, Gamez Beatriz, Platt Eleanor, Frost Lucy R, Allen Tiffany-Jayne, Marshall Gayle, Huber Kilian V M, Bauer Ludwig G, Vendrell Iolanda, Kessler Benedikt, Horne Anne, Reid Ian R, Bountra Chas, Kirkland James L, Khosla Sundeep, Hal Ebetino F, Roldan Emilio, Russell R Graham G, Edwards James R
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
bioRxiv. 2025 Mar 26:2025.03.25.645228. doi: 10.1101/2025.03.25.645228.
Bisphosphonates (BPs) have been the major class of medicines used to treat disorders of excessive bone loss for over five decades. Recently it has been recognized that BPs may also have additional significant beneficial extra-skeletal effects. These include a reduction of all-cause mortality and of conditions commonly linked to ageing, such as cancer and cardiovascular disease. Here we show that bisphosphonates co-localize with lysosomal and endosomal organelles in non-skeletal cells and stimulate cell growth at low doses. spatial transcriptomic analysis revealed differentially expressed senescence markers in multiple organs of aged BP-treated mice, and a shift in cellular composition toward those of young counterparts. Similarly, a 5000-plex plasma proteome analysis from osteopenic patients before and after BP-treatment showed significant alterations in ~400 proteins including GTPase regulators and markers of senescence, autophagy, apoptosis, and inflammatory responses. Furthermore, treatment with BPs protected against the onset of senescence . Proteome-wide target deconvolution using 2D thermal profiling revealed novel BP-binding targets (PHB2, ASAH1), and combined with RNA- and ATAC-seq of BP-treated cells and patient data, suggests downstream regulation of the MEF2A transcription factor within the heart. Collectively, these results indicate how BPs may beneficially modify the human plasma proteome, and directly impact multiple non-skeletal cell types through previously unidentified proteins, thereby influencing a range of pathways related to senescence and ageing.
五十多年来，双膦酸盐一直是用于治疗骨质过度流失疾病的主要药物类别。最近人们认识到，双膦酸盐可能还具有其他显著的有益的骨骼外效应。这些效应包括降低全因死亡率以及降低通常与衰老相关的疾病（如癌症和心血管疾病）的发生率。在此我们表明，双膦酸盐在非骨骼细胞中与溶酶体和内体细胞器共定位，并在低剂量时刺激细胞生长。空间转录组分析揭示了老年双膦酸盐治疗小鼠多个器官中差异表达的衰老标志物，以及细胞组成向年轻小鼠对应细胞组成的转变。同样，对骨质疏松患者双膦酸盐治疗前后进行的5000重血浆蛋白质组分析显示，约400种蛋白质有显著变化，包括GTP酶调节剂以及衰老、自噬、凋亡和炎症反应的标志物。此外，双膦酸盐治疗可预防衰老的发生。使用二维热分析进行蛋白质组范围内的靶点反卷积揭示了新的双膦酸盐结合靶点（PHB2、ASAH1），并结合双膦酸盐处理细胞的RNA测序和染色质转座酶可及性测序以及患者数据，提示心脏中MEF2A转录因子的下游调控。总体而言，这些结果表明双膦酸盐如何有益地改变人类血浆蛋白质组，并通过以前未鉴定的蛋白质直接影响多种非骨骼细胞类型，从而影响一系列与衰老相关的途径。
