Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment |
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| Institution: | 1. Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, United States;2. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States;3. Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, United States;4. Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States;1. Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland;2. Department of Endocrinology, Sahlgrenska University Hospital and Institute of Medicine, Sahlgrenska Academy, Sweden;3. Calcium Research Unit, Department of Food and Environmental Sciences (Nutrition), University of Helsinki, Helsinki, Finland;4. Department of Pediatrics, Children''s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland;5. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;6. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden;1. Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK;2. Department of Occupational Medicine, Headquarters Army Recruiting and Training Division, UK;3. Canadian Sport Institute-Pacific, Victoria, British Columbia, Canada;4. Cardiff School of Sport, Cardiff Metropolitan University, Cardiff, Wales, UK;5. Norwich Medical School, University of East Anglia, UK;1. Charles P. Darby Children''s Research Institute, Medical University of South Carolina, Charleston, SC, USA;2. Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA;3. Dept. of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA;4. College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA;1. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany;2. Laboratory of Pathophysiology, University of Antwerp, Wilrijk, Belgium;3. Institute for Laboratory Animal Science, Small Animal Imaging Center, Hannover Medical School, Hannover, Germany;4. University Children''s Hospital Rostock, University of Rostock, Germany |
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| Abstract: | Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown that bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical Wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3 week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly → Cys substitution on col1a1, for 5 weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI. |
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