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Putu Ustriyana1 Ziqiu Wang1 Kexun Chen1 Weilong Zhao1 Zhijun Xu1 Nita Sahai1 2 3

1, The University of Akron, Akron, Ohio, United States
2, The University of Akron, Akron, Ohio, United States
3, The University of Akron, Akron, Ohio, United States

Bone and dentin are composite materials with a high degree of hierarchical structure, which contributes largely to their biomechanical and biochemical properties. The tissues are composed of well-ordered self-assembled collagen fibrils as the organic template mineralized with uniaxially oriented and tightly packed HAP nanocrystals. It is widely accepted that unstructured acidic non-collagenous proteins (ANCPs) act as promoters or inhibitors of mineral deposition in the regulation of biomineralization. Osteocalcin (OCN) is a small, highly structured NCP that is found in abundance in bone. Recent findings have discovered that the partially carboxylated form of OCN is a multifunctional hormone, yet, surprisingly little is known about the detailed mechanisms by which the fully carboxylated form of OCN regulates mineralization. In this study, we focused on the potential roles of OCN in collagen fibrillogenesis and mineralization using various in vitro experimental methods. This NCP was found to regulate both collagen fibril formation and intrafibillar calcium-phosphate (Ca-PO4) mineralization. Results of fibrillogenesis and immunogold labeling studies showed that OCN was localized primarily in the intrafibrillar collagen matrix, especially at the boundary between the overlap and hole zones where crosslinking of collagen occurs. The mineralization studies revealed that OCN modulates mineralization by inhibiting rapid extrafibrillar Ca-PO4 particle precipitation. Transmission electron microscopy results showed that small, highly hydrated, OCN-stabilized spherical nanoclusters of Ca-PO4 were found on the outer surface of the fibrils. The nanoclusters are proposed to infiltrate the fibrils ultimately resulting in intrafibrillar mineralization with HAP crystals aligned with the fibrils and, at the same time, retarding rapid extrafibrillar mineralization. This mechanism is similar to that observed for unstructured ANCPs. The present findings contribute to understanding the multiple roles of OCN in regulating mineralization, as well as elucidating design principles of small synthetic analogs of OCN for promoting bone biomaterials at a reduced cost.

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