title: Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model.
authors: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
authors: Andreas
authors: A
authors: Roschger
authors: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
authors: Paul
authors: P
authors: Roschger
authors: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
authors: Petra
authors: P
authors: Keplingter
authors: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
authors: Klaus
authors: K
authors: Klaushofer
authors: Shriners Hospital for Children, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada.
authors: Sami
authors: S
authors: Abdullah
authors: Musculoskeletal Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors: Michaela
authors: M
authors: Kneissel
authors: Shriners Hospital for Children, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada. Electronic address: frauch@shriners.mcgill.ca.
authors: Frank
authors: F
authors: Rauch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: Bone formation; Osteogenesis imperfecta; Quantitative backscattered electron imaging; Sclerostin