title: How tough is brittle bone? Investigating osteogenesis imperfecta in mouse bone.
abstract: The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level, we attribute the loss in toughness to a decrease in the stabilizing enzymatic cross-links and an increase in nonenzymatic cross-links, which may break prematurely, inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales.
authors.affiliation: Department of Bioengineering, Imperial College London, U.K.|Materials Sciences Division, Lawrence Berkeley National Laboratory, U.S.A.|Department of Materials Science and Engineering, University of California Berkeley, U.S.A.
authors.forename: A
authors.initials: A
authors.lastname: Carriero
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, U.S.A.|Department of Materials Science and Engineering, University of California Berkeley, U.S.A.
authors.forename: E A
authors.initials: EA
authors.lastname: Zimmermann
authors.affiliation: Department of Earth Science and Engineering, Imperial College London, U.K.
authors.forename: A
authors.initials: A
authors.lastname: Paluszny
authors.affiliation: Department of Orthopaedic Surgery, University of California San Francisco, U.S.A.
authors.forename: S Y
authors.initials: SY
authors.lastname: Tang
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, U.S.A.|Department of Materials Science and Engineering, University of California Berkeley, U.S.A.
authors.forename: H
authors.initials: H
authors.lastname: Bale
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, U.S.A.|Department of Materials Science and Engineering, University of California Berkeley, U.S.A.
authors.forename: B
authors.initials: B
authors.lastname: Busse
authors.affiliation: Department of Orthopaedic Surgery, University of California San Francisco, U.S.A.
authors.forename: T
authors.initials: T
authors.lastname: Alliston
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, U.S.A.
authors.forename: G
authors.initials: G
authors.lastname: Kazakia
authors.affiliation: Materials Sciences Division, Lawrence Berkeley National Laboratory, U.S.A.|Department of Materials Science and Engineering, University of California Berkeley, U.S.A.
authors.forename: R O
authors.initials: RO
authors.lastname: Ritchie
authors.affiliation: Department of Bioengineering, Imperial College London, U.K.
authors.forename: S J
authors.initials: SJ
authors.lastname: Shefelbine
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001842:Bone and Bones / Q000473:pathology / Q000503:physiopathology* / Q000648:ultrastructure; D003198:Computer Simulation; D024022:Fibrillar Collagens / Q000378:metabolism; D050723:Fractures, Bone / Q000473:pathology / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010013:Osteogenesis Imperfecta / Q000473:pathology / Q000503:physiopathology*; D053838:Scattering, Small Angle; D017550:Spectroscopy, Fourier Transform Infrared; D014057:Tomography, X-Ray Computed; D014961:X-Ray Diffraction
chemical_list: D024022:Fibrillar Collagens; D017127:Glycation End Products, Advanced
keywords: BONE FRACTURE; BRITTLE BONE; CRACK GROWTH; CRACK INITIATION; FRACTURE MECHANICS; MOUSE BONE