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Background <p>Fracture healing is a complex biological process involving precisely coordinated phases of inflammation, cartilage formation, vascularization, and bone remodeling. Growing evidence suggests that non-coding RNAs play crucial regulatory roles in bone metabolism.</p> Objective <p>This study systematically investigated the role and molecular mechanisms of lncRNA GABARAPL2 (lnc_GABARAPL2) in fracture healing through integrated bioinformatics analysis, clinical validation, and functional experiments, with the goal of identifying novel biomarkers and therapeutic targets for impaired fracture healing.</p> Methods <p>Lnc_GABARAPL2, miR-302a-3p, RUNX2 and OCN mRNA expression levels were quantified by RT-qPCR. Osteogenic differentiation was assessed through Western blot (Collagen I) and spectrophotometric ALP activity measurement and alizarin red S-based mineralization assay. In vitro, lnc_GABARAPL2 expression was modulated in hBMSCs via siRNA knockdown and overexpression vectors, with target interaction validated by dual-luciferase reporter assay. Cell proliferation (CCK-8) and apoptosis (flow cytometry) were assessed. Statistical methods included t-tests, ANOVA, and ROC curve analysis.</p> Results <p>Lnc_GABARAPL2 expression was significantly elevated in non-union patients and demonstrated excellent predictive performance. Multivariate regression analysis confirmed lnc_GABARAPL2 as an independent predictor of non-union. Functional studies revealed that lnc_GABARAPL2 impaired osteogenic differentiation by suppressing ALP activity and reducing expression of key osteogenic markers RUNX2 and Collagen I, while modulating bone marrow mesenchymal stem cell proliferation and apoptosis through targeting miR-302a-3p.</p> Conclusion <p>These findings establish that lnc_GABARAPL2 may as a regulator of fracture healing and a promising predictive biomarker for non-union and targeting miR-302a-3p to modulate bone marrow mesenchymal stem cell functions, providing new insights for the development of RNA-based therapeutic strategies for impaired bone repair.</p>

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LncRNA GABARAPL2 promotes non‑union long bone fractures by suppressing bone mesenchymal stromal cell osteogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月7日

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  • Hurong Du,
  • Wenlong Zhang,
  • Zeyuan Liu,
  • Wei Liu

摘要

Background

Fracture healing is a complex biological process involving precisely coordinated phases of inflammation, cartilage formation, vascularization, and bone remodeling. Growing evidence suggests that non-coding RNAs play crucial regulatory roles in bone metabolism.

Objective

This study systematically investigated the role and molecular mechanisms of lncRNA GABARAPL2 (lnc_GABARAPL2) in fracture healing through integrated bioinformatics analysis, clinical validation, and functional experiments, with the goal of identifying novel biomarkers and therapeutic targets for impaired fracture healing.

Methods

Lnc_GABARAPL2, miR-302a-3p, RUNX2 and OCN mRNA expression levels were quantified by RT-qPCR. Osteogenic differentiation was assessed through Western blot (Collagen I) and spectrophotometric ALP activity measurement and alizarin red S-based mineralization assay. In vitro, lnc_GABARAPL2 expression was modulated in hBMSCs via siRNA knockdown and overexpression vectors, with target interaction validated by dual-luciferase reporter assay. Cell proliferation (CCK-8) and apoptosis (flow cytometry) were assessed. Statistical methods included t-tests, ANOVA, and ROC curve analysis.

Results

Lnc_GABARAPL2 expression was significantly elevated in non-union patients and demonstrated excellent predictive performance. Multivariate regression analysis confirmed lnc_GABARAPL2 as an independent predictor of non-union. Functional studies revealed that lnc_GABARAPL2 impaired osteogenic differentiation by suppressing ALP activity and reducing expression of key osteogenic markers RUNX2 and Collagen I, while modulating bone marrow mesenchymal stem cell proliferation and apoptosis through targeting miR-302a-3p.

Conclusion

These findings establish that lnc_GABARAPL2 may as a regulator of fracture healing and a promising predictive biomarker for non-union and targeting miR-302a-3p to modulate bone marrow mesenchymal stem cell functions, providing new insights for the development of RNA-based therapeutic strategies for impaired bone repair.