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

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dc.contributor.authorZhang, Y.-L.
dc.contributor.authorLiu, L.
dc.contributor.authorSu, Y.-W.
dc.contributor.authorXian, C.J.
dc.date.issued2021
dc.descriptionData source: Supplementary material, https://doi.org/10.3390/ijms222010988
dc.description.abstractIntensive 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, miR542-3p 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.
dc.description.statementofresponsibilityYa-Li Zhang, Liang Liu, Yu-Wen Su and Cory J. Xian
dc.identifier.citationInternational Journal of Molecular Sciences, 2021; 22(20):1-19
dc.identifier.doi10.3390/ijms222010988
dc.identifier.issn1422-0067
dc.identifier.issn1422-0067
dc.identifier.orcidZhang, Y.-L. [0000-0003-0107-4274]
dc.identifier.orcidXian, C.J. [0000-0002-8467-2845]
dc.identifier.urihttps://hdl.handle.net/2440/137534
dc.language.isoen
dc.publisherMDPI
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1127396
dc.rights© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
dc.source.urihttps://doi.org/10.3390/ijms222010988
dc.subjectmethotrexate; miRNA-542-3p; bone formation; marrow adiposity
dc.subject.meshBone and Bones
dc.subject.meshCell Line
dc.subject.meshAnimals
dc.subject.meshMice
dc.subject.meshRats
dc.subject.meshRats, Sprague-Dawley
dc.subject.meshMethotrexate
dc.subject.meshUbiquitin-Protein Ligases
dc.subject.meshIntercellular Signaling Peptides and Proteins
dc.subject.meshMembrane Proteins
dc.subject.meshMicroRNAs
dc.subject.mesh3' Untranslated Regions
dc.subject.meshCell Differentiation
dc.subject.meshDown-Regulation
dc.subject.meshOsteogenesis
dc.subject.meshModels, Biological
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshAdipogenesis
dc.subject.meshWnt Signaling Pathway
dc.subject.meshAntagomirs
dc.titlemiR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2
dc.typeJournal article
pubs.publication-statusPublished

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