miR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2

• Published in: International journal of molecular sciences 2021-10, Vol.22 (20), p.10988
• Main Authors: Zhang, Ya-Li, Liu, Liang, Su, Yu-Wen, Xian, Cory J
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Adipogenesis; Adipogenesis - drug effects; Adipose tissue; Animals; Annotations; Antagomirs - metabolism; Attenuation; Biomedical materials; Bone and Bones - metabolism; bone formation; Bone loss; Bone marrow; Bone turnover; Cell Differentiation - drug effects; Cell Line; Chemotherapy; Children; Down-Regulation - drug effects; Female; Frizzled-related protein 1; Genes; Genetic engineering; Homeostasis; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Leukemia; Ligands; Male; marrow adiposity; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Methotrexate; Methotrexate - pharmacology; Mice; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Mineralization; miRNA; miRNA-542-3p; Models, Biological; Osteogenesis; Osteogenesis - drug effects; Post-transcription; Proteins; Rats; Rats, Sprague-Dawley; Signal transduction; Stromal cells; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Wnt protein; Wnt Signaling Pathway - drug effects; β-Catenin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222010988

Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and miR-542-3p was recently shown to regulate osteogenesis in a bone loss context, the role of miR-542-3p in regulating osteogenesis and adipogenesis balance is not clear. Herein, in a rat MTX treatment-induced bone loss model, miR-542-3p was found significantly downregulated during the period of bone loss and marrow adiposity. Following target prediction, network construction, and functional annotation/ enrichment analyses, luciferase assays confirmed sFRP-1 and Smurf2 as the direct targets of miR-542-3p. miRNA-542-3p overexpression suppressed sFRP-1 and Smurf2 expression post-transcriptionally. Using in vitro models, miR-542-3p treatment stimulated osteogenesis but attenuated adipogenesis following MTX treatment. Subsequent signalling analyses revealed that miR-542-3p influences Wnt/β-catenin and TGF-β signalling pathways in osteoblastic cells. Our findings suggest that MTX treatment-induced bone loss and marrow adiposity could be molecularly linked to miR-542-3p pathways. Our results also indicate that miR-542-3p might be a therapeutic target for preserving bone and attenuating marrow fat formation during/after MTX chemotherapy.