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A direct role of collagen glycation in bone fracture.

Abstract

Non-enzymatic glycation (NEG) is an age-related process accelerated by diseases like diabetes, and causes the accumulation of advanced glycation end-products (AGEs). NEG-mediated modification of bone's organic matrix, principally collagen type-I, has been implicated in impairing skeletal physiology and mechanics. Here, we present evidence, from in vitro and in vivo models, and establish a causal relationship between collagen glycation and alterations in bone fracture at multiple length scales. Through atomic force spectroscopy, we established that NEG impairs collagen's ability to dissipate energy. Mechanical testing of in vitro glycated human bone specimen revealed that AGE accumulation due to NEG dramatically reduces the capacity of organic and mineralized matrix to creep and caused bone to fracture under impact at low levels of strain (3000-5000 μstrain) typically associated with fall. Fracture mechanics tests of NEG modified human cortical bone of varying ages, and their age-matched controls revealed that NEG disrupted microcracking based toughening mechanisms and reduced bone propagation and initiation fracture toughness across all age groups. A comprehensive mechanistic model, based on experimental and modeling data, was developed to explain how NEG and AGEs are causal to, and predictive of bone fragility. Furthermore, fracture mechanics and indentation testing on diabetic mice bones revealed that diabetes mediated NEG severely disrupts bone matrix quality in vivo. Finally, we show that AGEs are predictive of bone quality in aging humans and have diagnostic applications in fracture risk.

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  • Authors+Show Affiliations

    ,

    Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute Troy, Troy, NY 12180, USA.

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    Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute Troy, Troy, NY 12180, USA.

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    Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute Troy, Troy, NY 12180, USA; Middle East Technical University, Department of Engineering Sciences, Ankara, 06800, Turkey.

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    Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute Troy, Troy, NY 12180, USA.

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    Department of Mechanical Engineering, Villanova University, Villanova, PA 19085, USA.

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    Department of Medicine, Columbia University, New York, NY 10032, USA.

    Center for Biotechnology and Interdisciplinary Studies, Department of Biomedical Engineering, Rensselaer Polytechnic Institute Troy, Troy, NY 12180, USA. Electronic address: vashid@rpi.edu.

    Source

    MeSH

    Animals
    Biomechanical Phenomena
    Bone Matrix
    Calcification, Physiologic
    Collagen
    Diabetes Mellitus
    Energy Metabolism
    Female
    Femur
    Fractures, Bone
    Glycolysis
    Humans
    Mice
    Middle Aged

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    26530231

    Citation

    Poundarik, Atharva A., et al. "A Direct Role of Collagen Glycation in Bone Fracture." Journal of the Mechanical Behavior of Biomedical Materials, vol. 52, 2015, pp. 120-130.
    Poundarik AA, Wu PC, Evis Z, et al. A direct role of collagen glycation in bone fracture. J Mech Behav Biomed Mater. 2015;52:120-130.
    Poundarik, A. A., Wu, P. C., Evis, Z., Sroga, G. E., Ural, A., Rubin, M., & Vashishth, D. (2015). A direct role of collagen glycation in bone fracture. Journal of the Mechanical Behavior of Biomedical Materials, 52, pp. 120-130. doi:10.1016/j.jmbbm.2015.08.012.
    Poundarik AA, et al. A Direct Role of Collagen Glycation in Bone Fracture. J Mech Behav Biomed Mater. 2015;52:120-130. PubMed PMID: 26530231.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A direct role of collagen glycation in bone fracture. AU - Poundarik,Atharva A, AU - Wu,Ping-Cheng, AU - Evis,Zafer, AU - Sroga,Grazyna E, AU - Ural,Ani, AU - Rubin,Mishaela, AU - Vashishth,Deepak, Y1 - 2015/08/15/ PY - 2014/09/24/received PY - 2015/05/26/revised PY - 2015/05/30/accepted PY - 2015/11/5/entrez PY - 2015/11/5/pubmed PY - 2016/8/27/medline KW - Advanced glycation endproducts KW - Bone quality KW - Fracture mechanics KW - Non-enzymatic glycation KW - Type-I collagen SP - 120 EP - 130 JF - Journal of the mechanical behavior of biomedical materials JO - J Mech Behav Biomed Mater VL - 52 N2 - Non-enzymatic glycation (NEG) is an age-related process accelerated by diseases like diabetes, and causes the accumulation of advanced glycation end-products (AGEs). NEG-mediated modification of bone's organic matrix, principally collagen type-I, has been implicated in impairing skeletal physiology and mechanics. Here, we present evidence, from in vitro and in vivo models, and establish a causal relationship between collagen glycation and alterations in bone fracture at multiple length scales. Through atomic force spectroscopy, we established that NEG impairs collagen's ability to dissipate energy. Mechanical testing of in vitro glycated human bone specimen revealed that AGE accumulation due to NEG dramatically reduces the capacity of organic and mineralized matrix to creep and caused bone to fracture under impact at low levels of strain (3000-5000 μstrain) typically associated with fall. Fracture mechanics tests of NEG modified human cortical bone of varying ages, and their age-matched controls revealed that NEG disrupted microcracking based toughening mechanisms and reduced bone propagation and initiation fracture toughness across all age groups. A comprehensive mechanistic model, based on experimental and modeling data, was developed to explain how NEG and AGEs are causal to, and predictive of bone fragility. Furthermore, fracture mechanics and indentation testing on diabetic mice bones revealed that diabetes mediated NEG severely disrupts bone matrix quality in vivo. Finally, we show that AGEs are predictive of bone quality in aging humans and have diagnostic applications in fracture risk. SN - 1878-0180 UR - https://www.unboundmedicine.com/medline/citation/26530231/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S1751-6161(15)00283-0 DB - PRIME DP - Unbound Medicine ER -