When genetics redefine physiology

Osteocalcin has cardinal features of a hormone. It is synthesized in one single cell type, the osteoblast, acts at a distance in pancreatic β cells and Leydig cells of the testes, in these cells it needs to bind to a specific receptor we have identified to trigger a series of signaling events that culminate in the synthesis and secretion of insulin and testosterone respectively. Going beyond the defined boundaries of the initial working hypothesis we subsequently showed that osteocalcin convey the remarkable, even if unexpected, influence of the bone skeleton on brain development and function. As a matter of fact, osteocalcin is not only necessary but sufficient to promote cognitive functions in the mouse and to restore them to levels seen in young mice in older mice. This aspect of osteocalcin biology is mediated by a record receptor we have identified and studied the function.

The demonstration that osteocalcin is such a powerful regulator of brain development and functions represented a breach in the logic of the initial working hypothesis. This forced us to reassess not only the entire biology of osteocalcin but also what were the initial purposes of the classical functions of bone. The last conference of this cycle will present unpublished results that, because of their nature, provides a single conceptual framework that captures classical and endocrine functions of bone. We will end this cycle of conferences by highlighting some salient features of osteocalcin that distinguishes it from other hormones and that suggest that harnessing these pathways may potentially have great therapeutic impact on several age-related diseases ranging from sarcopenia to age-related memory loss.