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.
Highlights
Bone architecture adapts to changes in the mechanical strain engendered within it and by this means ensures that it becomes, and is maintained, sufficiently strong to withstand the loads to which it is subjected [1]
Local concentrations of IGF1 have not been shown to change following artificial mechanical loading [21,22], we have shown that loading increases the sensitivity of the IGF1receptor to ambient IGF1 in vitro [23]
We evaluated the effect of age and sex on both tibiae and changes [(right − left) / left] ∗ 100 due to loading in bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular pattern factor (Tb.Pf) in the trabecular region (0.25–0.75 mm distal to the proximal physis) and cortical bone area (Ct.Ar), total cross-sectional area inside the periosteal envelope (Tt.Ar), medullary area (Ma.Ar) and cortical thickness (Ct.Th) in the cortical site level demonstrating maximal bone formation following loading (37% from the proximal end) [41], according to ASBMR guidelines [46]
Summary
Bone architecture adapts to changes in the mechanical strain engendered within it and by this means ensures that it becomes, and is maintained, sufficiently strong to withstand the loads to which it is subjected [1]. This negative feedback mechanism is widely known as the mechanostat. The mechanostat is primarily a local phenomenon with local changes in loading-engendered strain culminating in local bone adaptation [2]. Bone architecture is influenced by endocrine and paracrine changes which may have their effect directly through the mechanisms of the mechanostat or by influencing the context in which the mechanostat operates [3].
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