Adaptive control of bone strength, common pathways for the effects of loading Estrogen and PTH. (360G-Wellcome-075430_Z_04_Z)

Post-menopausal osteoporosis is a crippling disease characterised by low bone mass, structurally inadequate bone architecture and a high incidence of fragility fractures. It represents a failure of the continuing ability of bone cells to use their response to mechanical strain as the controlling stimulus to adjust bone mass and architecture to successfully withstand the loading of the bone by which these strains are generated. The lifetime expectancy of a fracture for a 50 year old Caucasian American woman is 45 percent and a man 13 percent. In both sexes the severity of osteoporosis is related to the levels of available estrogen. We hypothesise that bone cells failure to maintain adequate bone mass when estrogen levels decline is because their adaptive response to strain uses the estrogen receptor and estrogen receptor number/activity is regulated by estrogen. As estrogen levels decline ER activity is reduced and bone cells' response to mechanical strain becomes less effective. This hypothesis is supported by our recent work in vivo showing the dependency of bones' adaptation to strain on ERa and in vitro the involvement of ERa on a number of bone cells' responses to mechanical stimulation including increase in cell number. The experiments in this proposal are designed to reveal the mechanisms by which the effects of strain in bone cells are processed by the ER, the extent to which ER number/activity is regulated by estrogen levels and/or strain history and the possibility of enhancing this response by ER agonists. We also aim to establish the relationship between the ER-mediated pathway used by strain and estrogen and the responsive cascades to other osteogenic influences, specifically the Wnt pathway and PTH. The Wnt pathway is important since mutations in its LRP-5 receptor are associated with bone mass in human families. PTH is important since intermittent treatment with PTH is a promising treatment for osteoporosis.