6533b857fe1ef96bd12b4476
RESEARCH PRODUCT
Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts.
Pierfrancesco TassonePierfrancesco TassoneEugenio MorelliMarco RossiAntonio GiordanoAntonio GiordanoDaniele CaraccioloMaria Teresa Di MartinoPierosandro TagliaferriNicola AmodioMaria Rita PitariMariamena ArbitrioAnnamaria GullaCiro BottaCinzia Federicosubject
Bone diseaseMessengerOsteoclastsTumor Microenvironment3' Untranslated RegionsMultiple myelomaTumorbiologyMesenchymal Stromal CellsRANKLProtein Inhibitors of Activated STATUp-Regulationmedicine.anatomical_structureOncologyRANKLmiRNAsmiR-21MiRNAMultiple MyelomaMiR-21; MiRNAs; Multiple myeloma bone disease; OPG; RANKL; 3' Untranslated Regions; Bone Marrow Cells; Bone Resorption; Cell Adhesion; Cell Line Tumor; Coculture Techniques; HEK293 Cells; Humans; Interleukin-6; Lentivirus; Mesenchymal Stromal Cells; MicroRNAs; Molecular Chaperones; Multiple Myeloma; Osteoclasts; Osteoprotegerin; Protein Inhibitors of Activated STAT; RANK Ligand; RNA Messenger; STAT3 Transcription Factor; Stromal Cells; Tumor Microenvironment; Up-Regulation; OncologyResearch Papermusculoskeletal diseasesSTAT3 Transcription FactorStromal cellBone Marrow CellsBone resorptionCell LineOsteoprotegerinCell Line TumormedicineCell AdhesionHumansRNA MessengerBone Resorptionbusiness.industryInterleukin-6LentivirusRANK LigandOsteoprotegerinMesenchymal Stem Cellsmedicine.diseaseMolecular medicineCoculture TechniquesMicroRNAsmultiple myeloma bone diseaseHEK293 CellsImmunologyCancer researchbiology.proteinRNAOPGBone marrowStromal CellsbusinessMolecular Chaperonesdescription
// Maria Rita Pitari 1 , Marco Rossi 1 , Nicola Amodio 1 , Cirino Botta 1 , Eugenio Morelli 1 , Cinzia Federico 1 , Annamaria Gulla 1 , Daniele Caracciolo 1 , Maria Teresa Di Martino 1 , Mariamena Arbitrio 2 , Antonio Giordano 3, 4 , Pierosandro Tagliaferri 1 , Pierfrancesco Tassone 1, 4 1 Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy 2 ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy 3 Department of Human Pathology and Oncology, University of Siena, Siena, Italy 4 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA Correspondence to: Pierfrancesco Tassone, e-mail: tassone@unicz.it Keywords: miR-21, miRNAs, multiple myeloma bone disease, OPG, RANKL Received: May 05, 2015 Accepted: June 11, 2015 Published: June 24, 2015 ABSTRACT miR-21 is an oncogenic microRNA (miRNA) with an emerging role as therapeutic target in human malignancies, including multiple myeloma (MM). Here we investigated whether miR-21 is involved in MM-related bone disease (BD). We found that miR-21 expression is dramatically enhanced, while osteoprotegerin (OPG) is strongly reduced, in bone marrow stromal cells (BMSCs) adherent to MM cells. On this basis, we validated the 3′UTR of OPG mRNA as miR-21 target. Constitutive miR-21 inhibition in lentiviral-transduced BMSCs adherent to MM cells restored OPG expression and secretion. Interestingly, miR-21 inhibition reduced RANKL production by BMSCs. Overexpression of protein inhibitor of activated STAT3 (PIAS3), which is a direct and validated target of miR-21, antagonized STAT3-mediated RANKL gene activation. Finally, we demonstrate that constitutive expression of miR-21 inhibitors in BMSCs restores RANKL/OPG balance and dramatically impairs the resorbing activity of mature osteoclasts. Taken together, our data provide proof-of-concept that miR-21 overexpression within MM-microenviroment plays a crucial role in bone resorption/apposition balance, supporting the design of innovative miR-21 inhibition-based strategies for MM-related BD.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-05-05 | Oncotarget |