Chlebek Carolyn, Raynor Maia S, Ross F Patrick, van der Meulen Marjolein C H
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853 United States.
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, 14853 United States.
JBMR Plus. 2025 Jun 14;9(9):ziaf105. doi: 10.1093/jbmrpl/ziaf105. eCollection 2025 Sep.
Applied in vivo loading, such as tibial compression, leads to robust bone formation in young rodents but diminished anabolic responses in adults. To evaluate age-related differences in biological pathways active with loading, we examined the metaphyseal transcriptomes following in vivo tibial compression in young (10-wk-old) and adult (26-wk-old) female C57Bl/6 mice. Animals underwent 1 bout tibial compression and were euthanized at 1, 3, or 24 h post-loading or loaded for 1 wk ( = 4-6/group). Differential gene expression and enriched biological processes were compared between loaded and contralateral control limbs. Few load-induced differentially expressed genes were shared between tissue compartments, across time points, and between young and adult mice. In young animals, the response of cancellous bone to loading was greater than the surrounding metaphyseal cortical shell at all timepoints examined. Following 1 bout of tibial compression, adults also had greater transcriptional responses in cancellous compared with cortical bone. However, load-induced gene expression was increased in the adult metaphyseal cortical shell compared with the cancellous core following 1 wk of loading. Despite previously established age-related reductions in the tissue-level response to loading, adults had 63% more load-induced differentially-expressed genes compared with young animals, 3919 vs 2402 total. Individual bone-associated gene expression in adults did not mirror the anabolic expression measured in young animals; the consistent load-induced upregulation of osteoblast genes in young animals was absent in adults. Most load-induced differentially expressed genes with high magnitude fold changes were novel with unknown roles in bone cells. The skeletally-relevant genes identified were related to osteoblast function and generally upregulated with loading. More bone-specific anabolic pathways were enriched with loading in cancellous compared to cortical bone. In conclusion, in both cancellous and cortical envelopes, adult mice have robust transcriptional responses to physiological loading that do not explain their reduced mechanoresponsiveness with age.
应用体内负荷，如胫骨压缩，可在幼年啮齿动物中导致强劲的骨形成，但在成年动物中合成代谢反应减弱。为了评估负荷激活的生物途径中与年龄相关的差异，我们检测了幼年（10周龄）和成年（26周龄）雌性C57Bl/6小鼠体内胫骨压缩后干骺端转录组。动物接受1次胫骨压缩，在负荷后1、3或24小时安乐死，或负荷1周（每组n = 4 - 6）。比较负荷侧与对侧对照肢体之间的差异基因表达和富集的生物学过程。在不同组织区域、不同时间点以及幼年和成年小鼠之间，很少有负荷诱导的差异表达基因是相同的。在幼年动物中，在所有检测的时间点，松质骨对负荷的反应都大于周围的干骺端皮质骨壳。在1次胫骨压缩后，与皮质骨相比，成年动物的松质骨转录反应也更大。然而，在负荷1周后，成年干骺端皮质骨壳中负荷诱导的基因表达相对于松质骨核心有所增加。尽管先前已确定与年龄相关的负荷组织水平反应降低，但成年动物负荷诱导的差异表达基因比幼年动物多63%，分别为3919个和2402个。成年个体骨相关基因表达与幼年动物中检测到的合成代谢表达并不一致；幼年动物中一致的负荷诱导成骨细胞基因上调在成年动物中不存在。大多数负荷诱导的高倍数变化差异表达基因是新基因，在骨细胞中的作用未知。鉴定出的与骨骼相关的基因与成骨细胞功能有关，通常随负荷而上调。与皮质骨相比，松质骨中更多的骨特异性合成代谢途径随负荷而富集。总之，在松质骨和皮质骨包膜中，成年小鼠对生理负荷都有强烈的转录反应，这并不能解释它们随年龄增长而降低的机械反应性。
