Behavioral signs of pain and functional impairment in a mouse model of osteogenesis imperfecta |
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| Institution: | 1. Faculty of Dentistry, McGill University, Montreal, QC, Canada;2. Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada;3. Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada;4. Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada;5. Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada;6. Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada;7. Department of Anaesthesiology, Faculty of Medicine, McGill University, Montreal, QC, Canada;1. McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States;2. Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, People''s Republic of China;3. Department of Orthopaedic Surgery, Wuhan General Hospital of Guangzhou Military Command, Hubei Province, People''s Republic of China;4. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States;5. Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States;1. St. Vincent''s Institute of Medical Research, Fitzroy, VIC, Australia;2. University of Melbourne, Department of Medicine at St. Vincent''s Hospital, Fitzroy, VIC, Australia;1. Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;2. Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA;3. Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USA;4. International Research Center for Advanced Structural and Bio-Materials, Beihang University, Beijing 100083, China;5. Department of Osteology and Biomechanics, University Medical Center Hamburg, D-22529 Hamburg, Germany;6. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;7. Department of Biomedical Engineering, Indiana University-Purdue University, Indianapolis (IUPUI), Indianapolis, IN 46202, USA;1. Postgraduation Program in Medicine, Medical Science, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil;2. Internal Medicine Division, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil;1. Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA;2. WIL Research Laboratories, Hillsborough, NC, USA;3. Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA;4. Department of Physiological Sciences, University of Florida, Gainesville, FL, USA;5. Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA |
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| Abstract: | Osteogenesis imperfecta (OI) is a congenital disorder caused most often by dominant mutations in the COL1A1 or COL1A2 genes that encode the alpha chains of type I collagen. Severe forms of OI are associated with skeletal deformities and frequent fractures. Skeletal pain can occur acutely after fracture, but also arises chronically without preceding fractures. In this study we assessed OI-associated pain in the Col1a1Jrt/+ mouse, a recently developed model of severe dominant OI. Similar to severe OI in humans, this mouse has significant skeletal abnormalities and develops spontaneous fractures, joint dislocations and vertebral deformities. In this model, we investigated behavioral measures of pain and functional impairment. Significant hypersensitivity to mechanical, heat and cold stimuli, assessed by von Frey filaments, radiant heat paw withdrawal and the acetone tests, respectively, were observed in OI compared to control wildtype littermates. OI mice also displayed reduced motor activity in the running wheel and open field assays. Immunocytochemical analysis revealed no changes between OI and WT mice in innervation of the glabrous skin of the hindpaw or in expression of the pain-related neuropeptide calcitonin gene-related protein in sensory neurons. In contrast, increased sensitivity to mechanical and cold stimulation strongly correlated with the extent of skeletal deformities in OI mice. Thus, we demonstrated that the Col1a1Jrt/+ mouse model of severe OI has hypersensitivity to mechanical and thermal stimuli, consistent with a state of chronic pain. |
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