Effects of Osteocalcin and Osteopontin on Damage Morphology and Bone Fragility

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DESCRIPTION (provided by applicant): Studies conducted under the parent grant suggest that non-collagenous matrix (NCPs) proteins including osteocalcin (OC) and osteopontin (OPN) act as link proteins to bone mineral and influence the initiation of bone fracture at the nanoscale These new findings suggest that the interaction of OC and OPN with hydroxyapatite mineral (HA) and with each other may influence organic-mineral interactions and determine bone's resistance against fracture (toughness). Both OC and OPN regulate mineralization in bone and the nature of their interactions with HA may also determine the structure and hydration of HA platelets in bone. Because fractures in bone are affected by the level of hydration and involve the deformation and disruption of the organic-mineral interface and protein-protein interactions, this information is critical to the understanding of bone quality and bone fragility. Thus the overall goal of this project is to determine the interaction of OC and OPN with hydroxyapatite mineral (HA) and with each other and evaluate their effects on the structure and hydration of HA platelets, organic-mineral interface and bone toughness. Bones of knockout mice (OC-/-, OPN-/-, OC-OPN-/-) and their WT littermates, available through the parent grant, as well as proteins (OC, OPN) will be subjected to Solid State Nuclear Magnetic Resonance (SS NMR) and Atomic Force Spectroscopy, Adsorption Chromatography or Fracture Mechanics Testing to determine whether: (H1) The interaction of OC and OPN with HA determines the structure and hydration of HA platelets and alters the organic-mineral interface in bone; and (H2) OC and OPN interact with HA and with each other to form the organic-mineral interface in bone and the strength of these bindings determines bone resistance against fracture (toughness). Consistent with the missions of NIAMS and this RFA-AR-13-003, a successful outcome of this project linking atomic level interactions to bone quality and fracture will lead to new approaches for preventing and repairing bone fractures. The new interdisciplinary team of a bone mechanics expert (Dr. Deepak Vashishth, PI on parent grant), a structural biologist and a solid state NMR expert (Dr. Scott McCallum) and a chemical engineer and an expert on hydroxyapatite-based column chromatography (Dr. Steven Cramer) will also help NIAMS to address new challenges in bone research.