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.

Public Health Relevance

Aging and disease may alter bone matrix and predispose an individual to a higher fracture risk. Based on the interactions of osteocalcin and osteopontin with mineral and with each other, this project will identify the organic-mineral interface as a new regulator for bone health. A successful outcome of this project will lead to new approaches for preventing and repairing bone fractures.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZAR1-KM (M1))
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Lester, Gayle E
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Rensselaer Polytechnic Institute
Biomedical Engineering
Schools of Engineering
United States
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Cleland, Timothy P; Vashishth, Deepak (2015) Bone protein extraction without demineralization using principles from hydroxyapatite chromatography. Anal Biochem 472:62-6
Sroga, Graýýyna E; Vashishth, Deepak (2012) Effects of bone matrix proteins on fracture and fragility in osteoporosis. Curr Osteoporos Rep 10:141-50
Jungmann, R; Szabo, M E; Schitter, G et al. (2011) Local strain and damage mapping in single trabeculae during three-point bending tests. J Mech Behav Biomed Mater 4:523-34
Sroga, Grazyna E; Karim, Lamya; Colon, Wilfredo et al. (2011) Biochemical characterization of major bone-matrix proteins using nanoscale-size bone samples and proteomics methodology. Mol Cell Proteomics 10:M110.006718
Karim, Lamya; Vashishth, Deepak (2011) Role of trabecular microarchitecture in the formation, accumulation, and morphology of microdamage in human cancellous bone. J Orthop Res 29:1739-44
Forwood, M R; Vashishth, D (2009) Translational aspects of bone quality--vertebral fractures, cortical shell, microdamage and glycation: a tribute to Pierre D. Delmas. Osteoporos Int 20 Suppl 3:S247-53
Vashishth, Deepak (2008) Small animal bone biomechanics. Bone 43:794-7
Tang, S Y; Vashishth, D (2007) A non-invasive in vitro technique for the three-dimensional quantification of microdamage in trabecular bone. Bone 40:1259-64
Vashishth, Deepak (2007) Hierarchy of Bone Microdamage at Multiple Length Scales. Int J Fatigue 29:1024-1033
Diab, Tamim; Vashishth, Deepak (2007) Morphology, localization and accumulation of in vivo microdamage in human cortical bone. Bone 40:612-8

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