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Differentially expressed miRNAs in bone after methotrexate treatment
Yali Zhang1, Liang Liu1, Katherine A Pillman2
1Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
Journal of Cellular Physiology
|September 13, 2021
Summary
Methotrexate (MTX) treatment causes bone loss and increased marrow fat. This study identified specific microRNAs (miRNAs), including miR-6315, involved in this bone/fat switch and found it targets Smad2, impacting TGF-β signaling.
Area of Science:
- Biomedical Sciences
- Molecular Biology
- Bone Biology
Background:
- Methotrexate (MTX) administration induces a "bone/fat switch," reducing bone volume and increasing marrow adiposity.
- The molecular mechanisms and recovery potential of MTX-induced bone changes remain unclear.
- MicroRNAs (miRNAs) are implicated in regulating osteogenic and adipogenic differentiation.
Purpose of the Study:
- To confirm the MTX-induced bone/fat switch in vitro.
- To identify specific miRNAs associated with MTX-induced bone damage and recovery in vivo.
- To elucidate the molecular pathways and regulatory networks involved in MTX-associated bone loss.
Main Methods:
- In vitro precursor cell culture models to confirm the bone/fat switch.
- A rat model with intensive daily MTX treatment over 14 days.
- miRNA array, RT-PCR, TargetScan, miRDB, STRING, Cytoscape, DAVID database, and dual-luciferase assays.
Main Results:
- Five upregulated miRNA candidates (miR-155-5p, miR-154-5p, miR-344g, miR-6215, miR-6315) were identified in MTX-treated rats.
- miR-6315 was identified as a key regulator, targeting Smad2.
- TGF-β signaling pathway was significantly enriched, with Smad2 as a direct target of miR-6315.
Conclusions:
- miR-6315 plays a vital role in regulating bone and marrow fat formation following MTX treatment.
- A comprehensive miRNA-mRNA regulatory network was constructed, offering insights into MTX-associated bone pathology.
- These findings may contribute to understanding the pathogenesis and prognosis of MTX-induced bone complications.
