title: Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-β Treatment.
abstract: Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-β signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-β treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-β treatment from both recessive (Crtap-/-) and dominant (Col1a2+/P.G610C) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-β treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2+/P.G610Cfemurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-β treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Bi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Grafe
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
authors.affiliation: Academic and Research Affairs, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Flores
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ming Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Catherine G
authors.initials: CG
authors.lastname: Ambrose
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D005799:Genes, Dominant; D005808:Genes, Recessive; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D011506:Proteins / Q000378:metabolism; D012044:Regression Analysis; D013059:Spectrum Analysis, Raman; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D055114:X-Ray Microtomography
chemical_list: C000619309:Col1a2 protein, mouse; D024042:Collagen Type I; C486354:Crtap protein, mouse; D016326:Extracellular Matrix Proteins; D018832:Molecular Chaperones; D011506:Proteins; D016212:Transforming Growth Factor beta
keywords: ANALYSIS/QUANTIFICATION OF BONE; BIOMECHANICS; MATRIX MINERALIZATION; OSTEOGENESIS IMPERFECTA; STATISTICAL METHODS