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Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts

2015; Impact Journals LLC; Volume: 6; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.4398

1949-2553

Maria Rita Pitari, Marco Rossi, Nicola Amodio, Cirino Botta, Eugenio Morelli, Cinzia Federico, Annamaria Gullà, Daniele Caracciolo, Maria Teresa Di Martino, Mariamena Arbitrio, Antonio Giordano, Pierosandro Tagliaferri, Pierfrancesco Tassone,

Bone Metabolism and Diseases

// Maria Rita Pitari 1 , Marco Rossi 1 , Nicola Amodio 1 , Cirino Botta 1 , Eugenio Morelli 1 , Cinzia Federico 1 , Annamaria Gullà 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.