Thakore Prachi, Karki Sangita, Hrdlicka Henry C, Garcia-Munoz John, Pereira Renata C, Delany Anne M
Center for Molecular Oncology, UConn Health, Farmington, CT 06030, USA.
Division of Pediatric Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Endocrinology. 2025 Jan 6;166(2). doi: 10.1210/endocr/bqaf008.
Glucocorticoid excess causes bone loss due to decreased bone formation and increased bone resorption; miR-433-3p is a microRNA (miRNA) that negatively regulates bone formation in male mice by targeting Runx2 as well as RNAs involved in Wnt, protein kinase A, and endogenous glucocorticoid signaling. To examine the impact of miR-433-3p on glucocorticoid-mediated bone loss, transgenic mice expressing a miR-433-3p tough decoy inhibitor in the osteoblast lineage were administered prednisolone via slow-release pellets. Bone loss was greater in control mice treated with prednisolone compared with miR-433-3p tough decoy mice due to higher osteoclast activity in the controls. In whole femurs, Rankl was significantly higher in prednisolone-treated controls compared with miR-433-3p tough decoy mice. Surprisingly, negative regulators of Wnt signaling Sost and Dkk1 were higher in miR-433-3p tough decoy mice and were unaffected by prednisolone. Luciferase- 3'-untranslated region reporter assays demonstrated that Sost is a novel miR-433-3p target, whereas Dkk1 is a previously validated miR-433-3p target. miR-433-3p levels are lower in matrix-synthesizing osteoblasts than in more osteocytic cells; thus the impact of miR-433-3p on the osteoblast lineage may be dependent on cell context: it is a negative regulator in matrix-depositing osteoblasts by targeting RNAs important for differentiation and function but a positive regulator in osteocytes, due to its ability to target prominently expressed negative regulators of Wnt signaling, Sost and Dkk1. The mechanisms by which miR-433-3p indirectly regulates glucocorticoid-mediated osteoclastogenesis remain unknown. However, we speculate that this regulation may be mediated by miR-433-3p activity in osteocytes, which play an important role in controlling osteoclastogenesis.
糖皮质激素过量会导致骨质流失，原因是骨形成减少和骨吸收增加；miR-433-3p是一种微小RNA（miRNA），它通过靶向Runx2以及参与Wnt、蛋白激酶A和内源性糖皮质激素信号传导的RNA来负向调节雄性小鼠的骨形成。为了研究miR-433-3p对糖皮质激素介导的骨质流失的影响，通过缓释微丸给在成骨细胞谱系中表达miR-433-3p强力诱饵抑制剂的转基因小鼠施用泼尼松龙。与miR-433-3p强力诱饵小鼠相比，用泼尼松龙治疗的对照小鼠骨质流失更严重，这是因为对照小鼠中的破骨细胞活性更高。在整个股骨中，泼尼松龙治疗的对照小鼠中的Rankl明显高于miR-433-3p强力诱饵小鼠。令人惊讶的是，Wnt信号传导的负调节因子Sost和Dkk1在miR-433-3p强力诱饵小鼠中更高，并且不受泼尼松龙的影响。荧光素酶-3'-非翻译区报告基因分析表明，Sost是一种新的miR-433-3p靶点，而Dkk1是先前已验证的miR-433-3p靶点。在基质合成成骨细胞中，miR-433-3p的水平低于更多骨细胞中的水平；因此，miR-433-3p对成骨细胞谱系的影响可能取决于细胞环境：它通过靶向对分化和功能重要的RNA在基质沉积成骨细胞中是负调节因子，但在骨细胞中是正调节因子，这是由于它能够靶向Wnt信号传导的显著表达的负调节因子Sost和Dkk1。miR-433-3p间接调节糖皮质激素介导的破骨细胞生成的机制仍然未知。然而，我们推测这种调节可能由骨细胞中的miR-433-3p活性介导，骨细胞在控制破骨细胞生成中起重要作用。
