Although lower bone mass is associated with increased bone fragility, studies conducted during the last grant cycle demonstrated that the mode and magnitude of microdamage formation affects bone's resistance to fracture or 'toughness'. Bones from younger donors are superior in toughness and form diffuse damage as the prominent morphology of microdamage. In contrast, bones from older donors predominantly form linear microcracks that coalesce to cause fracture. The basis of this unique association between damage morphology and toughness is not known. Our preliminary studies show for the first time that diffuse damage in bone initiates in the form of dilatational bands between the fused mineralized aggregates. Dilatational bands stain positive for osteocalcin (OC) and osteopontin (OPN). OC and OPN are present in higher amounts in diffuse damage areas than in controls and the deletion of OC or phosphorylation of bone matrix decreases toughness. Because OPN and OC vary with tissue and donor age, and are intimately associated with each other and with bone mineral where dilatational bands and diffuse damage form, the modification and loss of these non-collagenous matrix proteins may determine the damage morphology and bone's propensity to fracture. Thus the overall goal of this project is to investigate the role of OC and OPN in age-related bone fragility. Bones from human cadavers, aging mouse and transgenic (knock-outs-/- &hetrozygotes) mice including OC-/-, OC, OPN-/- OPN, OPN-OC-/- and OPN-OC and their controls will be subjected to mechanical and immunohistochemical evaluations to investigate whether: (H1): The deletion or modification of OC and or OPN in bone increases bone fragility and bone's propensity to form linear microcracks over diffuse damage;(H2) The age-related increase in bone fragility is associated with the modification and loss of OC and/or OPN that co-localize differently with diffuse damage and linear microcracks. Since OC and OPN levels can be manipulated through hormones and mechanical loading, the evidence of their new direct relationship to damage formation and bone fragility will lead to the development of novel modalities for predicting fracture, as well as strategies for improving bone quality and reducing the fracture risk.
Aging and disease may alter bone matrix and predispose an individual to a higher fracture risk. This project will identify the effects of the modifications and/or loss of two key bone proteins, osteocalcin and osteopontin, on age-related fragility fractures. This new information will lead to the development of novel modalities for predicting fracture, as well as strategies for improving bone quality and reducing the fracture risk.
|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, GraÅ¼yna 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, GraÅ¼yna 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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