Abstract
The strain imposed by mechanical loading on bone tissue normally stimulates a response by bone cells that results in an adjustment of bone architecture that enables the bone to withstand reasonable loads. But it is unclear why this process should become less effective in some 50 per cent of postmenopausal women, who suffer fractures as a result1. Here we show that bone in vivo undergoes an adaptive response to loading that is less effective in the absence of the α-form of the oestrogen receptor (ER-α) and that osteoblast-like cells require ER-α to proliferate in response to mechanical strain in vitro. As ER-α expression in osteoblasts and osteocytes depends on oestrogen concentration2,3,4,5, a failure to maintain bone strength after the menopause might be due to a reduction in the activity of ER-α in bone cells, thereby limiting their anabolic response to mechanical loading and allowing a loss of bone tissue comparable to that associated with disuse.
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We investigated bone's osteogenic response to loading in mice lacking functional ER-α. The normal peak locomotor strains (0.0026; length change as a proportion of original length) and strain rates (0.1 s−1) in the mouse ulna shaft were determined from surgically implanted strain gauges. We then loaded the ulnae of 20–24-week-old skeletally mature female mice through their olecranon and flexed carpus for three days a week for two weeks6. Each loading session comprised 40 repetitions of a 3.4-newton axial compressive load, which engendered peak strains (0.0028) and maximum strain rates (0.1 s−1) within the high physiological range.
In mice with normal ER-α function (ERα+/+ mice), this loading regimen stimulates sufficient new bone formation on the periosteal and endosteal surfaces to increase the cortical area at the midshaft by 8 ± 0.8% (P < 0.001; Fig. 1a). In their ERα−/− littermates, however, this response was diminished threefold (2.4 ± 0.4%; P < 0.001; Fig. 1b, c).
A single period of dynamic strain applied to monolayer cultures of osteoblast-like cells stimulates their proliferation, a response that is inhibited by ER blockers and increased by transfection with additional ER-α (ref. 7). We derived separate primary cultures of osteoblast-like cells from the ulnae of ERα−/− and ERα+/+ littermates and exposed them to a single 10-min period of mechanical strain (600 cycles, 1 Hz, 0.0034). Over the next 24 h, the number of ERα+/+ cells increased by 58 ± 34%, P = 0.050, whereas the number of ERα−/− cells did not increase. ERα−/− mice have fully functional oestrogen receptors of the β-form, indicating that ER-β does not compensate for incompetent ER-α in this response. However, a proliferation response to strain was conferred on ERα−/− cells by transfecting them with a functional human wild-type ER-α expression vector (pRST7-ER; ref. 8) (Fig. 1d).
These results obtained in vivo and in vitro indicate that strain-related responses by differentiated cells of the osteoblast lineage require ER-α activity. This might explain why postmenopausal women no longer maintain adequate bone mass — their bone cells are less responsive to mechanical stimulation owing to decreased ER-α activity.
The oestrogen receptor is the ancestral steroid receptor9, with one of its possible early reproductive functions being to induce skeletal remodelling to release calcium for egg-laying or embryonic development. The strain-sensitive mechanisms that now enable mammalian and avian skeletons to adapt to load-bearing might have developed later, exploiting this receptor's ability to influence bone (re)modelling activity.
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Lee, K., Jessop, H., Suswillo, R. et al. Bone adaptation requires oestrogen receptor-α. Nature 424, 389 (2003). https://doi.org/10.1038/424389a
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DOI: https://doi.org/10.1038/424389a
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