This project has two, intrinsically linked, goals. The first one is to identify cross-regulatory mechanisms between bone and pancreas morphogenesis during development. The second one is to assess whether this cross-regulation involves a maternal component. A growing body of studies has established the existence of a cross-talk of glucose and bone metabolisms during adulthood. On the one hand osteoblasts, the bone-forming cells, secrete a hormone, osteocalcin, regulating insulin synthesis and secretion among other processes. On the other hand, insulin signaling in osteoblasts regulates osteocalcin production and its resorption-mediated activation. Hence, during adulthood there is a feed-forward regulatory loop whereby insulin secretion by b-cells enhances the production and activity of osteocalcin, which in turns promotes insulin synthesis. More recently, we have shown that osteocalcin also controls b-cell proliferation in the developing embryo. Drawing a parallel with the functional crosstalk between bone cells and b-cells existing in adults, we hypothesize that a regulatory loop between osteocalcin and insulin could exist during development and could contribute to the formation of the skeleton and endocrine pancreas in the embryo. Accordingly, pups lacking insulin signaling in osteoblasts have a decrease in b-cell proliferation and lower serum levels of a biomarker of bone resorption compared to control littermates. Another recently identified feature of osteocalcin is its ability to cross the placenta during pregnancy and reach the embryo before it can produce its own. Hence, maternal osteocalcin could play a role in regulating insulin production and b- cell proliferation during pancreas development. In agreement with this hypothesis we have observed that adult Ocn+/- mice fed a high fat diet become more glucose intolerant when they are born from an Ocn-/- mother than from an Ocn+/- mother. Taken together, these novel findings and our preliminary data raise the prospect that maternal osteocalcin could initiate, or contribute to, a cross-regulation between osteocalcin and insulin that influences bone and pancreas development. To demonstrate this hypothesis we propose the following Specific Aims: 1. To determine whether maternal osteocalcin influences insulin production and b-cell proliferation in the embryo 2. To test whether insulin signaling in osteoblasts contributes to the regulation of b-cell proliferation by osteocalcin during development 3. To assess whether skeletogenesis is dependent of the embryonic production of insulin during development We would like to emphasize here that the genetically modified mouse models required to perform these studies have already been generated and therefore that achieving these aims can meet the timeline of a R21 project.
This project proposes to identify cross-regulatory mechanisms orchestrating the development of the skeleton bone and endocrine pancreas during embryogenesis. Our studies will also test whether the bone-derived hormone osteocalcin transferred from the mother to the embryo during pregnancy could contribute to this cross-regulation.
