title: Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta.
abstract: The Col1a2(+/G610C) knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2(+/G610C) and their wild-type controls (Col1a2(+/+)), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2(+/G610C) with an LRP(+/A214V) high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2(+/G610C) tibias had 13% fewer secondary trabeculae than Col1a2(+/+), these were thinner (11%) and more widely spaced (20%) than those of Col1a2(+/+) mice. Vertebrae of Col1a2(+/G610C) mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1(a2+/+). The cortical bone of Col1a2(+/G610C) tibias at 2-months had 3% higher tissue mineral density compared to Col1a2(+/+); Col1a2(+/G610C) vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2(+/+). FTIRI analysis, which provides information on bone chemical composition at ~7μm-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2(+/G610C) to Col1a2(+/+) at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2(+/G610C) vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution was noted in 10-day-old trabecular bone in vertebrae (31%) and in 2-month old trabecular bone in both tibia (31%) and vertebrae (4%). There was also a 16% lower carbonate-to-phosphate ratio in vertebral trabeculae and a correspondingly higher (22%) carbonate-to-phosphate ratio in 2month-old vertebral cortices. At age 3-months-of-age, male femurs with both a Col1a2(+/G610C) allele and a Lrp5 high bone mass allele (Lrp5+/A214V) showed an improvement in bone composition, presenting higher trabecular carbonate-to-phosphate ratio (18%) and lower trabecular and cortical acid-phosphate substitutions (8% and 18%, respectively). Together, these results indicate that mutant collagen α2(I) chain affects both bone quantity and composition, and the usefulness of this model for studies of potential OI therapies such as anti-sclerostin treatments.
authors.affiliation: Weill Cornell Medical College, New York, NY, United States. Electronic address: mam2147@med.cornell.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Masci
authors.affiliation: Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States. Electronic address: 19650877@qq.com.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States. Electronic address: ImbertL@HSS.edu.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Imbert
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States. Electronic address: Barnesai@mail.Nih.gov.
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.affiliation: Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States. Electronic address: SpevakM@HSS.edu.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Spevak
authors.affiliation: Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States. Electronic address: Lukashoval@HSS.edu.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Lukashova
authors.affiliation: Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States. Electronic address: Yihehuang@email.gwu.edu.
authors.forename: Yihe
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States. Electronic address: yanma@email.gwu.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States. Electronic address: oidoc@helix.nih.gov.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Division of Endocrinology and Genetics, Children's Hospital Boston, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States. Electronic address: Christina.jacobsen@childrens.harvard.edu.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Jacobsen
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States. Electronic address: Matthew.Warman@childrens.harvard.edu.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.affiliation: Weill Cornell Medical College, New York, NY, United States; Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States. Electronic address: Boskeya@HSS.edu.
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
mesh_terms: D000818:Animals; D001823:Body Composition; D015519:Bone Density; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism*; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000473:pathology; D004195:Disease Models, Animal; D005838:Genotype; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D008297:Male; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction; D017550:Spectroscopy, Fourier Transform Infrared; D055114:X-Ray Microtomography
chemical_list: C000619309:Col1a2 protein, mouse; D024042:Collagen Type I; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse
keywords: FTIRI; G610C mutation; Micro-computed tomography; Old order Amish mice; Osteogenesis imperfecta