title: Old age and the associated impairment of bones' adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle.
abstract: In old animals, bone's ability to adapt its mass and architecture to functional load-bearing requirements is diminished, resulting in bone loss characteristic of osteoporosis. Here we investigate transcriptomic changes associated with this impaired adaptive response. Young adult (19-week-old) and aged (19-month-old) female mice were subjected to unilateral axial tibial loading and their cortical shells harvested for microarray analysis between 1h and 24h following loading (36 mice per age group, 6 mice per loading group at 6 time points). In non-loaded aged bones, down-regulated genes are enriched for MAPK, Wnt and cell cycle components, including E2F1. E2F1 is the transcription factor most closely associated with genes down-regulated by ageing and is down-regulated at the protein level in osteocytes. Genes up-regulated in aged bone are enriched for carbohydrate metabolism, TNFα and TGFβ superfamily components. Loading stimulates rapid and sustained transcriptional responses in both age groups. However, genes related to proliferation are predominantly up-regulated in the young and down-regulated in the aged following loading, whereas those implicated in bioenergetics are down-regulated in the young and up-regulated in the aged. Networks of inter-related transcription factors regulated by E2F1 are loading-responsive in both age groups. Loading regulates genes involved in similar signalling cascades in both age groups, but these responses are more sustained in the young than aged. From this we conclude that cells in aged bone retain the capability to sense and transduce loading-related stimuli, but their ability to translate acute responses into functionally relevant outcomes is diminished.
authors.affiliation: School of Veterinary Sciences, University of Bristol, Bristol, UK.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Galea
authors.affiliation: School of Veterinary Sciences, University of Bristol, Bristol, UK. Electronic address: lee.meakin@bristol.ac.uk.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Meakin
authors.affiliation: Department of Periodontics & Cellular and Structural Biology, University of Texas Health Science Centre, San Antonio, USA.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Harris
authors.affiliation: School of Veterinary Sciences, University of Bristol, Bristol, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Delisser
authors.affiliation: School of Veterinary Sciences, University of Bristol, Bristol, UK.
authors.forename: Lance E
authors.initials: LE
authors.lastname: Lanyon
authors.affiliation: Department of Periodontics & Cellular and Structural Biology, University of Texas Health Science Centre, San Antonio, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: School of Veterinary Sciences, University of Bristol, Bristol, UK.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Price
mesh_terms: D000222:Adaptation, Physiological; D000375:Aging / Q000235:genetics / Q000473:pathology / Q000502:physiology*; D000818:Animals; D050260:Carbohydrate Metabolism / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013977:Tibia / Q000473:pathology / Q000503:physiopathology*; D059467:Transcriptome; D016474:Weight-Bearing / Q000502:physiology*
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse
keywords: Ageing; Bone; Mechanical loading; Proliferation