Bone-derived Sclerostin Regulates Glucose Metabolism Via Endocrine Actions in Pancreatic β- cells

Osteocyte (Ot)-derived Sclerostin (Scl), encoded by the SOST gene, regulates bone homeostasis by acting on osteoblasts, inhibiting bone formation and stimulating bone resorption. Emerging evidence suggest that Scl has additional functions in the regulation of glucose metabolism and fat mass. However, the data available is limited and contradictory, and the cellular and molecular mechanisms by which Scl regulates whole-body energy metabolism remain unclear. In this study, we hypothesize that Ots, through the secretion of Scl, communicate with pancreatic beta-cells to regulate glucose metabolism. We first examined glucose metabolism in mice with constitutive activation of beta-catenin in Ots, a mouse model characterized by high levels of Scl in bone and serum. daβcatOt mice exhibited a decrease in fasted blood glucose levels, impaired glucose tolerance response, and increased sensitivity to exogenous insulin administration. To determine the contribution of SOST/Scl to the altered glucose metabolism exhibited by daβcatOt mice, we next generated daβcatOt mice with global deletion of SOST (daβcatOt;SOSTKO), along with SOSTKO, daβcatOt, and control littermate mice. SOSTKO mice exhibited increased fasted glucose levels and improvement in glucose handling with no changes in the response to exogenous insulin. daβcatOt mice displayed the expected low glucose levels and impaired glucose metabolism. Importantly, genetic deletion of SOST in daβcatOt mice restored fasted glucose levels, glucose tolerance, and insulin sensitivity back to the levels of control mice, supporting the notion that Scl contributes to the regulation of glucose metabolism. Further, we found in vitro that treatment with Scl decreases viability and insulin mRNA gene expression in pancreatic beta-cells. Altogether, these results suggest that endocrine actions of Scl mediate the crosstalk between bone and pancreas and regulate glucose metabolism through direct actions in pancreatic beta-cells