Loss of milk fat globule-epidermal growth factor 8 (MFG-E8) in mice leads to low bone mass and accelerates ovariectomy-associated bone loss by increasing osteoclastogenesis |
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| Institution: | 1. Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Germany;2. Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Germany;3. Electron Microscopy Facility, Center for Regenerative Therapies Dresden, Germany;4. Dermatology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA;5. DFG Research Center for Regenerative Therapies Dresden, Germany;1. The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, 710032 Xi''an, Shaanxi, China;2. Center of Cardiology, Navy General Hospital, 100048 Beijing, China;1. Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA;2. Department of Orthopedics, Case Western Reserve University, Cleveland, OH 44106, USA;3. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA;1. Institute of Animal Physiology and Genetics CAS, v.v.i., Brno, Czech Republic;2. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic;3. Department of Physiology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic;4. Institute of Anatomy, Charles University, Prague, Czech Republic;5. Department of Craniofacial Development and Stem Cell Biology, King''s College London, London, UK;6. Department of Anatomy, Histology and Embryology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic;1. Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1795 Zonal Ave, Los Angeles, CA 90033, USA;2. Department of Medicine, Keck School of Medicine, University of Southern California, 1795 Zonal Ave, Los Angeles, CA 90033, USA;3. Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, 1795 Zonal Ave, Los Angeles, CA 90033, USA;4. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 1795 Zonal Ave, Los Angeles, CA 90033, USA;5. Metabolic Disorders Research, Amgen Inc., 1 Amgen Center Dr, Thousand Oaks, CA 91320, USA;6. UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA;7. Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 69978, Israel;1. IDIM, Instituto de Diagnóstico e Investigaciones Metabólicas, Buenos Aires, Argentina;2. Sección Intestino Delgado, Departamento de Medicina, Hospital de Gastroenterología “Dr. C. Bonorino Udaondo”, Buenos Aires, Argentina;3. Cátedra de Osteología y Metabolismo Mineral, Universidad del Salvador, Buenos Aires, Argentina;4. Cátedra de Gastroenterología Facultad de Medicina, Universidad del Salvador, Buenos Aires, Argentina;1. Seattle Children''s Research Institute, Center for Developmental Biology and Regenerative Medicine, Seattle, WA, USA;2. University of Washington, Center for Ecogenetics and Environmental Health, Seattle, WA, USA;3. Washington University, Department of Neurosurgery and St. Louis Children''s Hospital, St. Louis, MO, USA;4. School of Pharmacy, Pacific University, Hillsboro, OR, USA;5. Trialomics, Seattle, WA, USA;6. Seattle Children''s Craniofacial Center, Seattle, WA, USA |
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| Abstract: | Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that controls the engulfment of apoptotic cells and exerts inflammation-modulatory effects. Recently, it has been implicated in osteoclastogenesis and the pathogenesis of inflammatory periodontal bone loss, but its role in physiological bone homeostasis is still not well defined. Here, we evaluated the influence of MFG-E8 on osteoblasts and osteoclasts and its impact on bone remodeling in healthy and ovariectomized mice as a model for post-menopausal osteoporosis.Total and trabecular bone mineral densities at the lumbar spine in 6-week-old MFG-E8 KO mice were reduced by 11% (p < 0.05) and 17% (p < 0.01), respectively, as compared to wild-type (WT) mice. Accordingly, serum levels of the bone formation marker P1NP were decreased by 37% (p < 0.01) in MFG-E8 KO mice as were the ex vivo mineralization capacity and expression of osteoblast genes (Runx2, alkaline phosphatase, osteocalcin) in MFG-E8 KO osteoblasts. In contrast, serum bone resorption markers CTX1 and TRAP5b were increased by 30% and 60% (p < 0.05), respectively, in MFG-E8 KO mice. Furthermore, bone marrow macrophages from MFG-E8-KO mice differentiated more effectively into osteoclasts, as compared to WT cells. MFG-E8-deficient osteoclasts displayed increased bone resorption ex vivo, which could be reversed by the presence of recombinant MFG-E8. To determine the significance of the enhanced osteoclastogenesis in MFG-E8 KO mice, we performed an ovariectomy, which is associated with bone loss due to increased osteoclast activity. Indeed, MFG-E8 KO mice lost 12% more trabecular bone density than WT mice after ovariectomy.Together, these data indicate that MFG-E8 controls steady-state and pathological bone turnover and may therefore represent a new target gene in the treatment of bone diseases. |
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