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. 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.

The aim of the present study was to assess the bone regeneration process in defects introduced into rabbit long bones, which were regenerated with controlled release of recombinant bone morphogenetic protein‐2 (rBMP‐2). The orientation of the biological apatite (BAp) c‐axis and bone mineral density (BMD) were compared as predictors of bone mechanical function. A 20‐mm‐long defect was introduced in rabbit ulnas, and 17 µg of rBMP‐2 was controlled‐released into the defect using a biodegradable gelatin hydrogel as the carrier. In the bone regeneration process, two characteristic phases may have been governed by different factors. First, new bone formation actively occurred, filling the bone defect with newly formed bone tissue and increasing the BMD. This process was regulated by the strong osteoinductive capacity of rBMP‐2. Second, after filling of the defect and moderate BMD restoration, preferential BAp c‐axis orientation began to increase, coincident with initiation of remodeling. In addition, the BAp c‐axis orientation, rather than BMD, was strongly correlated with Young's modulus, an important index of bone mechanical function, particularly in the later stage of bone regeneration. Thus, preferential BAp c‐axis orientation is a strong determinant and predictor of the mechanical function of tissue‐engineered bone. Therefore, analysis of BAp preferential c‐axis orientation in addition to measurement of BMD is crucial in assessment of bone mechanical function. © 2013 American Society for Bone and Mineral Research © 2013 American Society for Bone and Mineral Research