Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling |
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| Institution: | 1. Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Zhejiang, China;2. Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China;3. Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA;4. Liaoning University of Traditional Chinese Medicine, Liaoning, China;5. Amgen Inc., Thousand Oaks, CA, USA;6. Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China;1. Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey;2. Division of Experimental Paediatric Endocrinology and Diabetes, University of Luebeck, Germany;3. Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA;1. Department of Reconstructive Sciences, University of Connecticut, Farmington, CT 06030, USA;2. Department of Immunology, University of Connecticut, Farmington, CT 06030, USA;3. Center on Aging, University of Connecticut, Farmington, CT 06030, USA;4. Department of Physiology and Immunology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia;1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 27212, USA;2. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA;3. Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA;4. Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;5. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;6. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;1. Department of Biomedical Engineering, College of Engineering and Medical School, University of Michigan, MI, USA;2. Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA;1. Skeletal Biology Laboratory, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR 97331, USA;2. Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA;3. Division of Biostatistics, Office of Surveillance and Biometrics, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, USA;4. Center for Healthy Aging Research, Oregon State University, Corvallis, OR 97331, USA;1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, USA;2. Department of Biostatistics, Indiana University School of Medicine, USA |
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| Abstract: | In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-cateninPrx1ER conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing process in CD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-cateninPrx1ER conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention. |
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