title: Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.
abstract: Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and animal age on bone quality.
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Ann Arbor, MI, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Sinder
authors.affiliation: Department of Chemistry, University of Michigan Ann Arbor, MI, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Lloyd
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Ann Arbor, MI, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Salemi
authors.affiliation: Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Caird
authors.affiliation: Department of Chemistry, University of Michigan Ann Arbor, MI, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Morris
authors.affiliation: Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan Ann Arbor, MI, USA. Electronic address: kenkoz@umich.edu.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kozloff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000473:pathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055119:Elastic Modulus / Q000187:drug effects; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008810:Mice, Inbred C57BL; D008903:Minerals / Q000378:metabolism; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008903:Minerals; C486030:Sost protein, mouse
keywords: Anabolic therapy; Bone quality; Nanoindentation; Osteogenesis imperfecta; Raman spectroscopy; Sclerostin antibody