Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta |
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| Affiliation: | 1. Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria;2. Shriners Hospital for Children, Montreal, Quebec, Canada;3. McGill University, Montreal, Quebec, Canada;4. Musculoskeletal Disease Area, Novartis Institutes for Biomedical Research, Basel, Switzerland;1. LTDS UMR CNRS 5513, Ecole Centrale Lyon, 36 avenue Guy de Collongue, 69134 Ecully, France;2. Department of Pediatric Orthopedics, Necker — Enfants Malades Hospital, AP-HP, Paris Descartes University, 145 rue de Sèvres, 75014 Paris, France;3. B2OA UMR CNRS 7052, University Paris-Diderot, 10 avenue de Verdun, 75010 Paris, France;1. Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USA;2. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, China;3. Department of Medicine, University of Wisconsin-Madison and Geriatric Research and Education Center, Madison, WI, USA;4. Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA;1. Weill Cornell Medical College, New York, NY, United States;2. Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States;3. National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States;4. Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States;5. Division of Endocrinology and Genetics, Children''s Hospital Boston, Boston, MA, United States;6. Department of Pediatrics, Harvard Medical School, Boston, MA, United States;7. Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children''s Hospital, Boston, MA, United States;1. Department of Cell & Molecular Medicine, Rush University Medical Center, Chicago, IL, United States of America;2. Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, United States of America |
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| 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 4 weeks in male Col1a1Jrt/+ mice, a model of severe dominant OI, starting either at 4 weeks (growing mice) or at 20 weeks (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 Col1a1Jrt/+ 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. |
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