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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
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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