Identification of Novel Cellular Pathways involved in Bone Mechanotransduction using Transcriptomics

306 pagesOsteoporosis is a disease resulting in decreased bone mass and mineralization. Anabolic, bone-forming therapeutics for osteoporosis have limited windows of efficacy, highlighting the need for new drugs. Mechanical loading stimulates bone formation in premenopausal women but has diminished effects in postmenopausal females. Similarly, loading in rodent models via in vivo tibial compression leads to robust bone formation in young animals but diminished responses in adults in both cortical and cancellous envelopes. Understanding the effects of mechanics and age on the load-induced biological responses could help identify new therapeutic targets. Transcriptomic profiles provide insight into biological pathways activated by mechanical loading. To examine the role of mechanics in load-induced transcriptomic responses of bone, we used young female mice. Tibial compression produces axially-varying deformations along cortical bone, inducing highest strains at the mid-diaphysis and lowest at the metaphyseal shell. We assessed load-induced gene expression in three cortical segments at early and late time points following tibial compression. The mid-diaphysis (highest strain) had the greatest transcriptomic response, with bone-related pathways initiated earliest and to the greatest extent compared to other segments. The metaphyseal shell (lowest strain) had the smallest transcriptomic response. To examine the effect of age on load-induced gene expression, we used young and adult female mice. We measured increased transcriptional activity in adults compared to young animals within cancellous bone and the surrounding metaphyseal cortical shell. At both ages, more pathways were activated by loading in cancellous bone compared to the cortical shell. Age-related differences within the cancellous bone, metaphyseal cortical shell, and mid-diaphysis highlighted dysregulation in bioenergetic pathways. To evaluate the contributions of bioenergetic pathways to load-induced bone formation, oxidative phosphorylation and glycolysis were individually inhibited in young and adult animals during two weeks of tibial compression. Analysis of bone mass and microarchitecture revealed different bioenergetic programs of cortical and cancellous bone; cortical bone area was reduced with oxidative phosphorylation inhibition whereas load-induced improvements of adult cancellous bone were dependent on glycolysis. This work demonstrates that both mechanics and age affect skeletal transcriptional responses and that gene expression can be used to identify novel pathways involved in load-induced bone formation.2024-06-0