Age-Related Impairment of Bones' Adaptive Response to Loading in Mice Is Associated With Sex-Related Deficiencies in Osteoblasts but No Change in Osteocytes

Abstract

Bones adjust their mass and architecture to be sufficiently robust to withstand functional loading by adapting to their strain environment. This mechanism appears less effective with age, resulting in low bone mass. In male and female young adult (17-week-old) and old (19-month-old) mice, we investigated the effect of age in vivo on bones' adaptive response to loading and in vitro in primary cultures of osteoblast-like cells derived from bone cortices. Right tibias were axially loaded on alternate days for 2 weeks. Left tibias were non-loaded controls. In a separate group, the number of sclerostin-positive osteocytes and the number of periosteal osteoblasts were analyzed 24 hours after a single loading episode. The responses to strain of the primary osteoblast-like cells derived from these mice were assessed by EGR2 expression, change in cell number and Ki67 immunofluorescence. In young male and female mice, loading increased trabecular thickness and the number of trabecular connections. Increase in the number of trabecular connections was impaired with age but trabecular thickness was not. In old mice, the loading-related increase in periosteal apposition of the cortex was less than in young ones. Age was associated with a lesser loading-related increase in osteoblast number on the periosteal surface but had no effect on loading-related reduction in the number of sclerostin-positive osteocytes. In vitro, strain-related proliferation of osteoblast-like cells was lower in cells from old than young mice. Cells from aged female mice demonstrated normal entry into the cell cycle but subsequently arrested in G2 phase, reducing strain-related increases in cell number. Thus, in both male and female mice, loading-related adaptive responses are impaired with age. This impairment is different in females and males. The deficit appears to occur in osteoblasts' proliferative responses to strain rather than earlier strain-related responses in the osteocytes. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation

“…In the current study, there was no bone formation evident on the periosteal surface of contralateral limb in Sham animals, which is consistent with previous studies showing that aged female C57BL/6J mice (26-week old) show diminished periosteal response and to lower periosteal apposition of the cortex due to reduced recruitment of osteoblasts to the periosteal surface compared in younger mice (10-week old) [32,68]. Axial loading elicited an anabolic response in the periosteal bone formation of Sham, but not IR animals, suggesting that HZE irradiation may have impaired load-induced periosteal bone formation at the tibia diaphysis.…”

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

“…This is the major characteristic of post-menopausal and age-related osteoporosis. Similar age-related deterioration in bone structure occurs in mice; 19-month-old mice have dramatic reductions in cortical and trabecular bone relative to 19-week-old mice (Meakin et al, 2014, Galea et al, 2015a). …”

“…This stimulus interacts with systemic influences to orchestrate the activity of osteoblasts and osteoclasts in order to locally maintain bone's functional integrity. Mechanisms that could contribute to the age-related imbalance between bone formation and resorption include impaired osteocyte function and/or impaired osteoblast responses to “osteogenic cues”, including those resulting from mechanical simulation (Meakin et al, 2014). Mechanical loading triggers many acute responses, including the transcriptional regulation of hundreds of genes (Zaman et al, 2009).…”

“…We have recently demonstrated that several acute responses of osteoblastic lineage cells to mechanical strain are not significantly different between young and aged mice, including down-regulation of the Wnt antagonist sclerostin in osteocytes, up-regulation of the transcription factor Egr2, and entry of osteoblastic cells into the cell cycle (Meakin et al, 2014). If old age has little effect on the initial responses to strain this would suggest that age–related deterioration in the effectiveness of (re)modelling is due to reduced functional responses to the stimulus that strain engenders.…”

Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice

“…From the ex vivo data, a peak load [in Newtons (N)] corresponding to 3,500 Ϯ 150 ε at the gauge site was used for the 19-mo-old mice, and 2,800 Ϯ 500 ε at the gauge site was used for the 6-mo-old mice in the in vivo loading experiments. A higher strain at the gauge site was used in 19-mo-oldmice based on previous findings that, if a similar strain is applied, mechanical loading will produce a lower osteogenic response in older female mice compared with younger female mice (15). Therefore, we used a higher strain at the gauge site in the 19-mo-old mice to have comparable osteogenic responses to mechanical loading in both age groups of mice.…”