Transplanted mesenchymal stromal cells are unable to migrate to the bone surface and subsequently improve osteogenesis in glucocorticoid-induced osteoporosis |
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| Institution: | 1. Department of Cell Biology, Zunyi Medical University, Zunyi, Guizhou Province, China;2. Department of Orthopedic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;1. Department of Cardiology, Rostock University Medical Center, Rostock, Germany;2. Department of Cardiac Surgery, Rostock University Medical Center, Rostock, Germany;3. Department of Life, Light and Matter, University of Rostock, Rostock, Germany;4. Institute of Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany;1. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China;2. Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China;3. Cancer Institute, Xuzhou Medical University, Xuzhou, China;4. Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China;1. Center for Cellular Engineering, Department of Transfusion Medicine and Center for Cellular Engineering, National Instates of Health Clinical Center, Bethesda, Maryland, USA;2. Department of Medicine (Hematology Division), University of Washington/Fred Hutchinson Cancer Center, Seattle, Washington, USA;1. School of Management, Guangzhou University, Guangzhou, China;2. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia;3. Independent Researcher, India;4. Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia;5. Master''s Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia;6. Dr Soetomo General Academic Hospital, Surabaya, Indonesia;7. Department of Physiology, Ferghana Medical Institute of Public Health, Ferghana, Uzbekistan;8. Department of Mathematics, Dwaraka Doss Goverdhan Doss Vaishnav College, University of Madras, Chennai, India;9. Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia;10. Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh, Egypt;11. Al-Manara College for Medical Sciences, Maysan, Iraq;12. Department of Anesthesia Techniques, Al-Mustaqbal University College, Babylon, Iraq;13. Al-Nisour University College, Baghdad, Iraq;14. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq;15. Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia;1. Department of Hematology, Singapore General Hospital, Singapore, Republic of Singapore;2. Department of Clinical and Translational Research, Singapore General Hospital, Singapore, Republic of Singapore;3. Patient Services, Blood Services Group, Health Sciences Authority, Singapore, Republic of Singapore;4. Cell Therapy Facility, Blood Services Group, Health Sciences Authority, Singapore, Republic of Singapore;5. Infection and Immunity Clinical Academic Group, St George''s, University of London, London, UK |
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| Abstract: | Long-term or high-dose use of glucocorticoids causes bone loss and low bone formation. We previously demonstrated that dexamethasone (Dex) administration caused the shifted differentiation balance of mesenchymal stromal cells (MSCs) to favor adipogenic lineage over osteoblastic lineage, which is one of the key mechanisms for Dex-induced osteoporosis (DIO). These findings indicate that supplementing functional allogeneic MSCs could be a therapeutic strategy for DIO. Here, we found that transplanting MSCs by intramedullary injection had little effect in promoting new bone formation. Fluorescent-labeled lineage tracing revealed that 1 week after transplantation, green fluorescent protein (GFP)-MSCs were found to migrate to the bone surface (BS) in control mice but not in DIO mice. As expected, GFP-MSCs on the BS were mostly Runx2-positive; however, GFP-MSCs located away from the BS failed to differentiate into osteoblasts. We further discovered that the levels of transforming growth factor beta 1 (TGF-β1), one of the main chemokines for MSC migration, is significantly decreased in the bone marrow fluid of DIO mice, which is insufficient to direct MSC migration. Mechanistically, Dex inhibits TGF-β1 expression by down-regulating its promoter activity, which decreases bone matrix–deposited TGF-β1 as well as active TGF-β1 released during osteoclast-mediated bone resorption. This study indicates that blocking MSC migration in osteoporotic BM contributes to bone loss and suggests that MSC mobilization to the BS may be a promising target for treating osteoporosis. |
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