Joris Virginie, Balmayor Elizabeth R, van Griensven Martijn
Department of Cell Biology-Inspired Tissue Engineering (cBITE), MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, the Netherlands.
Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany.
Mol Ther Nucleic Acids. 2025 Jan 3;36(1):102446. doi: 10.1016/j.omtn.2024.102446. eCollection 2025 Mar 11.
Bone metabolism is highly regulated, and microRNAs (miRs) can contribute to this process. Among them, miR-125b is well known to enhance osteoporosis and reduce osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this work, we aim to evaluate and understand how miR-125b modulates mineralization of hMSCs in two different models. Cells were cultured in dexamethasone or calcium medium and transfected with miR-125b mimic. Exposure to dexamethasone or calcium medium increased the mineralization of hMSCs and was associated with decreased miR-125b expression. Transfection of miR-125b mimic in dexamethasone-treated cells increased mineralization, while it decreased it in calcium-treated cells. Levels of osteogenic markers presented the same difference. We identified STAT3, p53, and RUNX2 as direct targets of miR-125b in hMSCs. While these targets remained identical in both treatments, their modulation after transfection was different. We showed that miR-125b mimicking differentially modulated the expression of the miR-199a/214 cluster, probably via STAT3/miR-199a/214 and p53/miR-214 pathways. In conclusion, miR-125b affinity for targets implicated in bone remodeling changed depending on the models used to induce mineralization and led to opposite physiological effects. This work shows the complexity of drugs such as dexamethasone and opens the door for new models of mineralization.
骨代谢受到高度调控，微小RNA（miR）可参与这一过程。其中，miR-125b因会加重骨质疏松并降低人间充质干细胞（hMSCs）的成骨分化而广为人知。在本研究中，我们旨在评估并了解miR-125b如何在两种不同模型中调节hMSCs的矿化作用。将细胞培养于地塞米松或钙培养基中，并用miR-125b模拟物进行转染。暴露于地塞米松或钙培养基可增加hMSCs的矿化作用，并与miR-125b表达降低相关。在地塞米松处理的细胞中转染miR-125b模拟物会增加矿化作用，而在钙处理的细胞中则会降低矿化作用。成骨标志物水平呈现相同差异。我们确定信号转导和转录激活因子3（STAT3）、p53和 runt相关转录因子2（RUNX2）为hMSCs中miR-125b的直接靶点。虽然在两种处理中这些靶点保持一致，但其转染后的调节情况有所不同。我们表明，miR-125b模拟物可能通过STAT3/miR-199a/214和p53/miR-214途径对miR-199a/214簇的表达进行差异调节。总之，miR-125b对参与骨重塑的靶点的亲和力因用于诱导矿化的模型而异，并导致相反的生理效应。这项工作揭示了地塞米松等药物的复杂性，并为新的矿化模型打开了大门。
