title: Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts.
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.
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Pitari
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Federico
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gullà
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Caracciolo
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.affiliation: ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy.
authors.forename: Mariamena
authors.initials: M
authors.lastname: Arbitrio
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
mesh_terms: D020413:3' Untranslated Regions; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology*; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C508600:IL6 protein, human; D015850:Interleukin-6; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D018832:Molecular Chaperones; D053244:Osteoprotegerin; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D053245:RANK Ligand; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human
keywords: OPG; RANKL; miR-21; miRNAs; multiple myeloma bone disease