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; Thomas, Corinne J; Gundberg, Caren M et al. (2016) Influence of carboxylation on osteocalcin detection by mass spectrometry. Rapid Commun Mass Spectrom 30:2109-15
Pizzoccaro, Marie-Alix; Nikel, Ondrej; Sene, Saad et al. (2016) Adsorption of benzoxaboroles on hydroxyapatite phases. Acta Biomater 41:342-50
Sroga, Grażyna E; Vashishth, Deepak (2016) A strategy to quantitate global phosphorylation of bone matrix proteins. Anal Biochem 499:85-9
Jepsen, Karl J; Silva, Matthew J; Vashishth, Deepak et al. (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951-66
Ural, A; Janeiro, C; Karim, L et al. (2015) Association between non-enzymatic glycation, resorption, and microdamage in human tibial cortices. Osteoporos Int 26:865-73
Morgan, Stacyann; Poundarik, Atharva A; Vashishth, Deepak (2015) Do Non-collagenous Proteins Affect Skeletal Mechanical Properties? Calcif Tissue Int 97:281-91
Sroga, Grażyna E; Siddula, Alankrita; Vashishth, Deepak (2015) Glycation of human cortical and cancellous bone captures differences in the formation of Maillard reaction products between glucose and ribose. PLoS One 10:e0117240
Cleland, Timothy P; Vashishth, Deepak (2015) Bone protein extraction without demineralization using principles from hydroxyapatite chromatography. Anal Biochem 472:62-6
Poundarik, Atharva A; Vashishth, Deepak (2015) Multiscale imaging of bone microdamage. Connect Tissue Res 56:87-98
Nikel, Ondrej; Laurencin, Danielle; McCallum, Scott A et al. (2013) NMR investigation of the role of osteocalcin and osteopontin at the organic-inorganic interface in bone. Langmuir 29:13873-82

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