The regulation in bone cells of sost/sclerostin by mechanical strain

Under normal circumstances bones are kept strong enough to withstand mechanical loads without fracture because bone cells sense the deformation that occurs when they are loaded and adjust bone structure accordingly. This process of functional adaptation allows us to lead active lives without a high incidence of fracture. The situation changes in later life when age-related bone loss occurs, leading to osteoporosis. Current treatments are unable to recover the bone lost with age, nor can they selectively target bone formation to regions of the skeleton under the greatest strain. Clinical trials are currently investigating the potential of blocking sclerostin, an endogenous inhibitor of bone formation which is down-regulated by loading, to cause bone formation. However, the mechanisms by which sclerostin expression is controlled by loading are not known. The experiments in this thesis were designed to establish how osteocyte-like cells translate the mechanical strain signals they encounter during loading into appropriate down-regulation of Sostlsclerostin. These studies delineate novel mechanisms whereby prostaglandin and oestrogen receptor signalling, previously known to influence bone's adaptation to loading, cooperate to promote Sost down-regulation following strain. We demonstrate that sclerostin inhibits the proliferation of osteoblast-like cells following strain, providing a mechanism whereby blocking sclerostin may lead to new bone formation. In the absence of sclerostin, osteoblastic cells' proliferation following strain requires the oestrogen receptor a and protein kinase Ca. Strain also orients the division of these cells through Planar Cell Polarity signalling, thereby potentially influencing bone architecture. These findings identify new mechanisms whereby loading stimulates bone cells to produce a structure strong enough to resist fracture. Deciphering the cellular processes by which sclerostin is naturally down-regulated following loading may lead to the development of improved treatment regimens for bone loss diseases based on the combination of sclerostin blocking therapies with other bone-strengthening strategies such as exercise.