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 1 h and 24 h 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.

Parathyroid hormone's enhancement of bones' osteogenic response to loading is affected by ageing in a dose- and time-dependent manner

“…This emphasises the importance of being careful when extrapolating responses in young animals to those in old ones. This may be particularly true in the case of PTH as we have recently reported basal and loading-responsive transcriptomic differences between tibiae of young and aged mice [31]. These include Wnt signalling and bioenergetics processes, both of which are involved in the anabolic effects of PTH [32], [33].…”

Decreased pericellular matrix production and selection for enhanced cell membrane repair may impair osteocyte responses to mechanical loading in the aging skeleton

“…Adaptation to mechanical loading is important for maintaining bone health throughout life, and impairments to bone adaptation responses, such as with aging, can contribute to diseases like osteoporosis. Previous studies indicate that bone's mechanosensing osteocytes are lost with aging (Galea et al, ; Mullender, van der Meer, Huiskes, & Lips, ; Tiede‐Lewis et al, ), and that surviving osteocytes may have impaired mechanotransduction responses (Chalil et al, ; Donahue, Jacobs, & Donahue, ; Holguin, Brodt, & Silva, ). Accordingly, while mechanical loading of bone via exercise is an effective method to increase peak bone mass in younger individuals (Greene et al, ; Kontulainen, Sievanen, Kannus, Pasanen, & Vuori, ; Warden et al, ; Weatherholt & Warden, ), exercise‐based approaches produce modest effects (at best) on bone properties in elderly subjects (Gomez‐Cabello, Ara, Gonzalez‐Aguero, Casajus, & Vicente‐Rodriguez, ; Karlsson, ).…”

“…Several causative factors for this blunted mechanical adaption phenomenon with aging have been suggested. For example, one study showed that aged cortical bone demonstrated an altered transcriptional response following mechanical loading, with a suppression of functional signaling cascades and a blunted activation timeframe downstream of loading as compared to loaded bones from younger subjects (Galea et al, ). Even in a sedentary state, aged cortical bone demonstrated an upregulation of TGF‐beta signaling and inflammatory TNF‐alpha signaling pathways, and a downregulation of Wnt pathway components and genes related to cell cycle progression (Galea et al, ).…”

Genetic Variability affects the Skeletal Response to Unloading

“…This is similar to the response seen after anabolic mechanical loading. 36-38 It is possible that at the time point analyzed, bones had reached a homeostasis where they were no longer perceiving a decrease in mechanical loading and were beginning to remodel. Although there was increased expression of osteogenic genes, the new bone formation in immobilized bones is likely to be of lower quality than in the controls.…”