Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA.
J Bone Miner Res. 2022 Nov;37(11):2277-2287. doi: 10.1002/jbmr.4686. Epub 2022 Sep 17.
Osteoporosis affects over 200 million women worldwide, one-third of whom are predicted to suffer from an osteoporotic fracture in their lifetime. The most promising anabolic drugs involve administration of expensive antibodies. Because mechanical loading stimulates bone formation, our current data, using a mouse model, replicates the anabolic effects of loading in humans and may identify novel pathways amenable to oral treatment. Murine tibial compression produces axially varying deformations along the cortical bone, inducing highest strains at the mid-diaphysis and lowest at the metaphyseal shell. To test the hypothesis that load-induced transcriptomic responses at different axial locations of cortical bone would vary as a function of strain magnitude, we loaded the left tibias of 10-week-old female C57Bl/6 mice in vivo in compression, with contralateral limbs as controls. Animals were euthanized at 1, 3, or 24 hours post-loading or loaded for 1 week (n = 4-5/group). Bone marrow and cancellous bone were removed, cortical bone was segmented into the metaphyseal shell, proximal diaphysis, and mid-diaphysis, and load-induced differential gene expression and enriched biological processes were examined for the three segments. At each time point, the mid-diaphysis (highest strain) had the greatest transcriptomic response. Similarly, biological processes regulating bone formation and turnover increased earlier and to the greatest extent at the mid-diaphysis. Higher strain induced greater levels of osteoblast and osteocyte genes, whereas expression was lower in osteoclasts. Among the top differentially expressed genes at 24-hours post-loading, 17 had known functions in bone biology, of which 12 were present only in osteoblasts, 3 exclusively in osteoclasts, and 2 were present in both cell types. Based on these results, we conclude that murine tibial loading induces spatially unique transcriptomic responses correlating with strain magnitude in cortical bone. © 2022 American Society for Bone and Mineral Research (ASBMR).
全世界有超过 2 亿女性受到骨质疏松症的影响，预计其中三分之一的人在一生中会遭受骨质疏松性骨折。最有前途的合成代谢药物涉及昂贵抗体的给药。由于机械加载刺激骨形成，我们当前的数据使用小鼠模型复制了人类加载的合成代谢效应，并且可能确定了可通过口服治疗的新途径。小鼠胫骨压缩会在皮质骨上产生轴向变化的变形，在中轴骨处引起最大应变，在近侧骨壳处引起最小应变。为了测试加载引起的皮质骨不同轴向位置的转录组反应是否随应变幅度而变化的假设，我们在体内对 10 周龄雌性 C57Bl/6 小鼠的左胫骨进行了压缩加载，对侧肢体作为对照。动物在加载后 1、3 或 24 小时或加载 1 周后（每组 n=4-5）被安乐死。取出骨髓和松质骨，将皮质骨分割为近侧骨壳、近端骨干和中轴骨干，并检查三个节段的加载诱导的差异基因表达和丰富的生物学过程。在每个时间点，中轴骨干（最大应变）具有最大的转录组反应。同样，调节骨形成和转化的生物学过程在中轴骨干处更早且最大程度地增加。较高的应变诱导更高水平的成骨细胞和破骨细胞基因，而破骨细胞的表达较低。在加载后 24 小时的差异表达基因中，有 17 个基因具有已知的骨生物学功能，其中 12 个仅存在于成骨细胞中，3 个仅存在于破骨细胞中，2 个存在于两种细胞类型中。基于这些结果，我们得出结论，小鼠胫骨加载会在皮质骨中诱导与应变幅度相关的空间独特的转录组反应。
