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Sclerostin Regulation,Microarchitecture, and Advanced Glycation End-Products in the Bone of Elderly Women With Type 2 Diabetes |
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| Authors: | Alessandra Piccoli Francesca Cannata Rocky Strollo Claudio Pedone Giulia Leanza Fabrizio Russo Valentina Greto Camilla Isgrò Carlo Cosimo Quattrocchi Carlo Massaroni Sergio Silvestri Gianluca Vadalà Tiziana Bisogno Vincenzo Denaro Paolo Pozzilli Simon Y Tang Matt J Silva Caterina Conte Rocco Papalia Mauro Maccarrone Nicola Napoli |
| Affiliation: | 1. Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Unit of Biochemistry and Molecular Biology, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Investigation, Methodology, Writing - original draft;2. Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy;3. Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Conceptualization, Funding acquisition, Validation, Writing - review & editing;4. Unit of Geriatrics, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Formal analysis, Methodology, Writing - review & editing;5. Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Investigation, Methodology, Writing - review & editing;6. Unit of Orthopedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Investigation, Methodology;7. Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Investigation, Methodology;8. Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari “Aldo Moro”, Bari, Italy Contribution: Investigation, Methodology;9. Department of Medicine, Unit of Radiology, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Funding acquisition, Methodology;10. Research Unit of Measurements and Biomedical Instrumentation, Departmental Faculty of Bioengineering, Campus Bio-Medico di Roma University, Rome, Italy Contribution: Investigation, Methodology;11. Research Unit of Measurements and Biomedical Instrumentation, Departmental Faculty of Bioengineering, Campus Bio-Medico di Roma University, Rome, Italy Contribution: Funding acquisition, Validation;12. Unit of Orthopedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Conceptualization, Methodology;13. Endocannabinoid Research Group, Institute of Translational Pharmacology, National Research Council, (CNR), Rome, Italy Contribution: Investigation, Methodology;14. Unit of Orthopedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Supervision;15. Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Funding acquisition, Supervision;16. Unit of Orthopedics, Washington University in St. Louis, St. Louis, MO, USA Contribution: Investigation, Methodology, Writing - review & editing;17. Unit of Orthopedics, Washington University in St. Louis, St. Louis, MO, USA;18. Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy;19. Unit of Orthopedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy Contribution: Funding acquisition, Supervision;20. Unit of Biochemistry and Molecular Biology, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy European Center for Brain Research (CERC)/Santa Lucia Foundation, Rome, Italy Contribution: Funding acquisition, Supervision |
| Abstract: | Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Whether the expression of the sclerostin-encoding SOST gene is altered in T2D, and whether it is associated with AGEs accumulation or regulation of other bone formation-related genes is unknown. We hypothesized that AGEs accumulate and SOST gene expression is upregulated in bones from subjects with T2D, leading to downregulation of bone forming genes (RUNX2 and osteocalcin) and impaired bone microarchitecture and strength. We obtained bone tissue from femoral heads of 19 T2D postmenopausal women (mean glycated hemoglobin [HbA1c] 6.5%) and 73 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. Despite similar bone mineral density (BMD) and biomechanical properties, we found a significantly higher SOST (p = .006) and a parallel lower RUNX2 (p = .025) expression in T2D compared with non-diabetic subjects. Osteocalcin gene expression did not differ between T2D and non-diabetic subjects, as well as circulating osteocalcin and sclerostin levels. We found a 1.5-fold increase in total bone AGEs content in T2D compared with non-diabetic women (364.8 ± 78.2 versus 209.9 ± 34.4 μg quinine/g collagen, respectively; p < .001). AGEs bone content correlated with worse bone microarchitecture, including lower volumetric BMD (r = −0.633; p = .02), BV/TV (r = −0.59; p = .033) and increased trabecular separation/spacing (r = 0.624; p = .023). In conclusion, our data show that even in patients with good glycemic control, T2D affects the expression of genes controlling bone formation (SOST and RUNX2). We also found that accumulation of AGEs is associated with impaired bone microarchitecture. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. © 2020 American Society for Bone and Mineral Research (ASBMR). |
| Keywords: | BIOMECHANICS BONE μCT DIABETES OSTEOBLASTS SCLEROSTIN |