title: HBM Mice Have Altered Bone Matrix Composition and Improved Material Toughness.
abstract: The G171V mutation in the low-density lipoprotein receptor-related protein 5 (LRP5) leads to a high bone mass (HBM) phenotype. Studies using HBM transgenic mouse models have consistently found increased bone mass and whole-bone strength, but little attention has been paid to the composition of the bone matrix. The current study sought to determine if the cortical bone matrix composition differs in HBM and wild-type mice and to determine how much of the variance in bone material properties is explained by variance in matrix composition. Consistent with previous studies, HBM mice had greater cortical area, moment of inertia, ultimate force, bending stiffness, and energy to failure than wild-type animals. The increased energy to failure was primarily caused by a large increase in post-yield behavior, with no difference in pre-yield behavior. The HBM mice had increased mineral-to-matrix and collagen cross-link ratios, and decreased crystallinity, carbonate, and acid phosphate substitution as measured by Fourier transform infrared microspectroscopy, but no differences in crystal length, intra-fibular strains, and mineral spacing compared to wild-type controls, as measured by X-ray scattering. The largest between genotype difference in material properties was a twofold increase in the modulus of toughness in HBM mice. Step-wise regression analyses showed that the specific matrix compositional parameters most closely associated with material properties varied between the wild-type and HBM genotypes. Although the mechanisms controlling the paradoxical combination of more mineralized yet tougher bone in HBM mice remain to be fully explained, the findings suggest that LRP5 represents a target to not only build bone mass but also to improve bone quality.
authors.affiliation: Department of Anatomy & Cell Biology, Rush University Medical Center, 600 South Paulina, Suite 507, Chicago, IL, 60612, USA. ryan_ross@rush.edu.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Ross
authors.affiliation: Department of Anatomy & Cell Biology, Rush University Medical Center, 600 South Paulina, Suite 507, Chicago, IL, 60612, USA.|Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Mashiatulla
authors.affiliation: Center for Advanced Radiation Sources, The University of Chicago, Chicago, IL, USA.|National Synchrotron Light Source, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Alvin S
authors.initials: AS
authors.lastname: Acerbo
authors.affiliation: X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Almer
authors.affiliation: National Synchrotron Light Source, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Miller
authors.affiliation: Department of Oral Biology, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Department of Anatomy & Cell Biology, Rush University Medical Center, 600 South Paulina, Suite 507, Chicago, IL, 60612, USA.|Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA.|Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: D Rick
authors.initials: DR
authors.lastname: Sumner
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001857:Bone Matrix / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D005260:Female; D005269:Femur / Q000378:metabolism; D005838:Genotype; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D012044:Regression Analysis; D017550:Spectroscopy, Fourier Transform Infrared; D055114:X-Ray Microtomography; D014965:X-Rays
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D003094:Collagen
keywords: Collagen cross-linking; HBM; LRP5; Matrix composition; Mineralization; Toughness