Molecular Identification of Spatially Distinct Anabolic Responses to Mechanical Loading in Murine Cortical Bone
Molecular Identification of Spatially Distinct Anabolic Responses to Mechanical Loading in Murine Cortical Bone
复制标题
小鼠皮质骨对机械负荷的空间差异性合成代谢反应的分子鉴定
DOI：
10.1002/jbmr.4686
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发表时间：
2022-09-17
影响因子：
6.2
通讯作者：
van der Meulen, Marjolein C. H.
中科院分区：
文献类型：
--
作者：
Chlebek, Carolyn;Moore, Jacob A.;van der Meulen, Marjolein C. H.
骨质疏松症影响着全世界2亿多妇女，其中三分之一预计在其一生中遭受骨质疏松性骨折。最有前途的合成代谢药物涉及昂贵的抗体管理。由于机械负荷刺激骨形成，我们目前的数据，使用小鼠模型，复制了人类负荷的合成代谢作用，并可能确定适合口服治疗的新途径。小鼠胫骨压缩产生轴向变化的变形沿着皮质骨，诱导最高的应变在中间骨干和最低的干骺端壳。为了检验在皮质骨的不同轴向位置处的负荷诱导的转录组学响应将作为应变幅度的函数而变化的假设，我们在体内以压缩方式加载10周龄雌性C57 Bl/6小鼠的左胫骨，以对侧肢体作为对照。动物在加载后1、3或24小时处以安乐死或加载1周（n = 4-5只/组）。取出骨髓和松质骨，将皮质骨分割成干骺端壳、近端骨干和中段骨干，并检查这三段的负荷诱导差异基因表达和丰富的生物学过程。在每个时间点，中间骨干（最高菌株）具有最大的转录组学反应。同样，生物过程调节骨形成和营业额增加更早，并在最大程度上在中间骨干。更高的应变诱导成骨细胞和骨细胞基因的水平更高，而破骨细胞的表达较低。在加载后24小时的最高差异表达基因中，17个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，小鼠胫骨负荷诱导空间上独特的转录组学反应与皮质骨中的应变幅度相关。(c)2022年美国骨与矿物质研究学会（ASBMR）。
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. (c) 2022 American Society for Bone and Mineral Research (ASBMR).