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靶向FSHR的LncRNA MRF通过调节cAMP-PKA-CREB信号通路抑制骨髓间充质干细胞的成骨分化和骨缺损修复。

LncRNA MRF targeting FSHR inhibits the osteogenic differentiation of BMSCs and bone defect repair through the regulation of the cAMP-PKA-CREB signaling pathway.

作者信息

Ning Qing, Li Ming, Liao Zhuangyao, Chen Enming, Liu Huatao, Liang Yuwei, Chen Yuanquan, Li Yuxi, Huang Lin

机构信息

Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.

出版信息

Stem Cell Res Ther. 2025 Apr 23;16(1):200. doi: 10.1186/s13287-025-04291-9.

DOI:10.1186/s13287-025-04291-9
PMID:40264197
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12016372/
Abstract

BACKGROUND

Mesenchymal stem cells (MSCs), known for their ability to differentiate into osteoblasts, play a pivotal role in bone metabolism. In our previous investigations, we identified a novel long non-coding RNA (lncRNA) named MCP1 Regulatory Factor (MRF), which exhibits significant involvement in immune regulation of BMSCs. Moreover, we observed noticeable expression changes of MRF during the osteogenic differentiation of BMSCs. However, the exact role and underlying mechanism of MRF in the osteogenic differentiation of BMSCs remain elusive.

METHODS

QRT-PCR analysis was employed to assess the expression levels of MRF. RNA interference and overexpression plasmids were utilized to modulate MRF expression, allowing for the observation of changes in the osteogenic differentiation capacity of BMSCs. Downstream pathways involved in the MRF-mediated regulation of BMSCs' osteogenic differentiation were predicted using transcriptome sequencing. The functionality of MRF in vivo was validated through a mouse tibial drilling defect model.

RESULTS

In patients with osteoporosis, there is a notable increase in the expression of MRF within BMSCs. During the osteogenic differentiation of BMSCs, the MRF expression progressively decreases. The knockdown of MRF significantly enhances the osteogenic differentiation of BMSCs, promoting an increased expression of bone-related proteins such as RUNX2, ALP, and COL1A1. Transcriptome sequencing and western blot indicated that cAMP/PKA/CREB signaling pathway was significantly activated after lncRNA-MRF knockdown. Moreover, in the mouse tibial drilling defect model, MRF knockdown significantly promotes ossification in vivo.

CONCLUSIONS

MRF modulates the cAMP/PKA/CREB signaling pathway via the follicle stimulating hormone receptor (FSHR), thereby influencing the ossification differentiation of BMSCs. Our research suggests that MRF may serve as a potential target for bone-related disorders.

摘要

背景

间充质干细胞（MSCs）以其分化为成骨细胞的能力而闻名，在骨代谢中起关键作用。在我们之前的研究中，我们鉴定了一种名为MCP1调节因子（MRF）的新型长链非编码RNA（lncRNA），它在骨髓间充质干细胞（BMSCs）的免疫调节中发挥着重要作用。此外，我们观察到MRF在BMSCs成骨分化过程中表达有明显变化。然而，MRF在BMSCs成骨分化中的确切作用和潜在机制仍不清楚。

方法

采用实时定量聚合酶链反应（QRT-PCR）分析来评估MRF的表达水平。利用RNA干扰和过表达质粒来调节MRF的表达，从而观察BMSCs成骨分化能力的变化。使用转录组测序预测参与MRF介导的BMSCs成骨分化调节的下游途径。通过小鼠胫骨钻孔缺损模型验证MRF在体内的功能。

结果

在骨质疏松症患者中，BMSCs内MRF的表达显著增加。在BMSCs成骨分化过程中，MRF表达逐渐降低。敲低MRF显著增强BMSCs的成骨分化，促进骨相关蛋白如RUNX2、碱性磷酸酶（ALP）和I型胶原蛋白（COL1A1）的表达增加。转录组测序和蛋白质免疫印迹表明，lncRNA-MRF敲低后，环磷酸腺苷/蛋白激酶A/环磷腺苷反应元件结合蛋白（cAMP/PKA/CREB）信号通路被显著激活。此外，在小鼠胫骨钻孔缺损模型中，敲低MRF显著促进体内骨化。

结论

MRF通过卵泡刺激素受体（FSHR）调节cAMP/PKA/CREB信号通路，从而影响BMSCs的骨化分化。我们的研究表明，MRF可能成为骨相关疾病的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/82be3eaa4d36/13287_2025_4291_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/d0e15120abf3/13287_2025_4291_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/d50ca2efb49e/13287_2025_4291_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/e2c54e8f6b5f/13287_2025_4291_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/b98d32c7679c/13287_2025_4291_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/c6d49f40aa23/13287_2025_4291_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/82be3eaa4d36/13287_2025_4291_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/d0e15120abf3/13287_2025_4291_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/d50ca2efb49e/13287_2025_4291_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/e2c54e8f6b5f/13287_2025_4291_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/b98d32c7679c/13287_2025_4291_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/c6d49f40aa23/13287_2025_4291_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3570/12016372/82be3eaa4d36/13287_2025_4291_Fig6_HTML.jpg

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