Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong University, No.44-1 Wenhua Road West, Jinan, Shandong, 250012, China.
Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.
Cell Mol Life Sci. 2024 Oct 5;81(1):423. doi: 10.1007/s00018-024-05453-3.
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 Ca influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca 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.
活性维生素 D 以促进骨质疏松症而闻名，根据最新证据，其具有免疫调节作用。依骨化醇（ED-71）是第三代新型活性维生素 D 类似物的代表，其改善糖尿病性骨质疏松症的具体免疫机制尚不清楚。我们在此评估了 ED-71 在 2 型糖尿病（T2DM）背景下的治疗效果，深入探讨了其潜在机制。在 T2DM 小鼠模型中，ED-71 可减轻骨丢失和骨髓脂肪变性。同时，它纠正了失衡的葡萄糖稳态和血脂异常，改善了胰岛β细胞损伤和肝糖脂代谢紊乱。随后，在注射 Treg 细胞耗竭剂 CD25 的小鼠中，我们观察到 ED-71 的上述有益作用部分依赖于 Treg 亚群比例。在机制上，ED-71 促进 CD4 T 细胞向 Treg 亚群分化，促进 Ca 内流和 ORAI1 和 STIM1 的表达，这是钙库操纵性钙内流（SOCE）的关键蛋白。SOCE 抑制剂 2-APB 部分减弱了 ED-71 对上述结果的积极影响。总体而言，ED-71 调节 SOCE 介导的 Treg 细胞分化，同时实现改善糖尿病性骨质疏松症和糖脂代谢紊乱的双重目的，展示了其在骨免疫治疗和涉及 SOCE 的疾病干预方面的潜力。
