The skeletal transcriptional response to mechanical load varies with age and tissue compartment in female mice

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 (n = 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.