Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass

The strength of bone depends on bone quantity and quality. Osteocalcin (Ocn) is the most abundant noncollagenous protein in bone and is produced by osteoblasts. It has been previously claimed that Ocn inhibits bone formation and also functions as a hormone to regulate insulin secretion in the pancreas, testosterone synthesis in the testes, and muscle mass. We generated Ocn-deficient (Ocn(-/-)) mice by deleting Bglap and Bglap2. Analysis of Ocn(-/-)mice revealed that Ocn is not involved in the regulation of bone quantity, glucose metabolism, testosterone synthesis, or muscle mass. The orientation degree of collagen fibrils and size of biological apatite (BAp) crystallites in the c-axis were normal in the Ocn(-/-)bone. However, the crystallographic orientation of the BAp c-axis, which is normally parallel to collagen fibrils, was severely disrupted, resulting in reduced bone strength. These results demonstrate that Ocn is required for bone quality and strength by adjusting the alignment of BAp crystallites parallel to collagen fibrils; but it does not function as a hormone. Author summary The strength of bone depends on both its quantity and quality. Osteocalcin (Ocn) is the most abundant non-collagenous protein in bone, but its function remains unclear. Earlier studies by other investigators have suggested that Ocn decreases the quantity of bone by decreasing bone formation; and in addition it works as a hormone to regulate glucose metabolism, testosterone synthesis, and muscle mass in distant tissues. We have generated Ocn-deficient mice and show herein that Ocn is not required for bone formation. It is, however, required for optimal bone quality and strength. Specifically, we show that in the Ocn-deficient mice collagen fibers align normally, but apatite crystallites align randomly against collagen, resulting in disorganized mineralization and reduced bone strength. Furthermore, we show that glucose metabolism, testosterone synthesis, and muscle mass are normal in the Ocn-deficient mice. We conclude that Ocn acts in bone to optimize its quality and strength, but not quantity. And, in contrast to earlier claims, it does not work as a hormone to control glucose metabolism, testosterone synthesis, and muscle mass.