1. Eldecalcitol ameliorates diabetic osteoporosis and glucolipid metabolic disorder by promoting Treg cell differentiation through SOCE.
- Author
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Jiang Y, Gao R, Ying Q, Li X, Dai Y, Song A, Liu H, Hasegawa T, and Li M
- Subjects
- Animals, Male, Mice, Calcium metabolism, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental complications, Glycolipids pharmacology, Glycolipids therapeutic use, Mice, Inbred C57BL, ORAI1 Protein metabolism, Stromal Interaction Molecule 1 metabolism, Cell Differentiation drug effects, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Osteoporosis drug therapy, Osteoporosis metabolism, Osteoporosis pathology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory metabolism, T-Lymphocytes, Regulatory immunology, Vitamin D analogs & derivatives, Vitamin D pharmacology, Vitamin D therapeutic use
- Abstract
Active vitamin D, known for its role in promoting osteoporosis, has immunomodulatory effects according to the latest evidence. Eldecalcitol (ED-71) is a representative of the third-generation novel active vitamin D analogs, and its specific immunological mechanisms in ameliorating diabetic osteoporosis remain unclear. We herein evaluated the therapeutic effects of ED-71 in the context of type 2 diabetes mellitus (T2DM), delving into its underlying mechanisms. In a T2DM mouse model, ED-71 attenuated bone loss and marrow adiposity. Simultaneously, it rectified imbalanced glucose homeostasis and dyslipidemia, ameliorated pancreatic β-cell damage and hepatic glycolipid metabolism disorder. Subsequently, in mice injected with the Treg cell-depleting agent CD25, we observed that the beneficial effects of ED-71 mentioned earlier were partially contingent on the Treg subsets ratio. Mechanistically, ED-71 promoted the differentiation of CD4
+ T cells into Treg subsets, facilitating Ca2+ influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca2+ entry (SOCE). The SOCE inhibitor, 2-APB, partially attenuated the positive effects of ED-71 observed in the above results. Overall, ED-71 regulates SOCE-mediated Treg cell differentiation, accomplishing the dual purpose of simultaneously ameliorating diabetic osteoporosis and glucolipid metabolic disorders, showcasing its potential in osteoimmunity therapy and interventions for diseases involving SOCE., (© 2024. The Author(s).)- Published
- 2024
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