Bone Gla protein increases HIF-1α-dependent glucose metabolism and induces cartilage and vascular calcification

Objective-: Bone Gla Protein (BGP, osteocalcin) is commonly present in the calcified vasculature and was recently shown as energy metabolism-regulating hormone. This study investigates the role of BGP in cartilage and vasculature mineralization. Methods and results-: We established an in vitro BGP-overexpression model in chondrocytes (ATDC5) and vascular smooth muscle cells (MOVAS). BGP overexpression upregulated markers of chondrogenic differentiation and intensified staining for minerals. BGP overexpression enhanced glucose uptake and increased expression of glucose transporters and glycolysis enzymes while decreasing gluconeogenesis enzymes. Treatment with purified BGP activated insulin signaling pathway and upregulated genes of glucose transport and utilization. Both BGP overexpression and treatment with purified BGP resulted in stabilization of hypoxia-inducible factor 1α (HIF-1α) in chondrocytes and vascular smooth muscle cells, shown essential in mediating the direct metabolic effect of BGP. The in vivo model of 1,25(OH)2D3-induced vascular calcification in rats revealed a correlation between calcification, elevated BGP levels, and increased HIF-1α expression in aortas and bone growth plates. The in vivo introduction of BGP siRNA, coadministered with 1,25(OH)2D3, prevented 1,25(OH)2D3-induced HIF-1α stabilization, and diminished osteochondrogenic differentiation and mineralization of aortas. Conclusion-: This study demonstrates novel mechanism by which BGP locally shifts cells toward glycolytic breakdown of glucose, in a HIF-1α-dependent manner, and stimulates calcification of cartilage and vasculature.