Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts
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Maria Rita Pitari1, Marco Rossi1, Nicola Amodio1, Cirino Botta1, Eugenio Morelli1, Cinzia Federico1, Annamaria Gullà1, Daniele Caracciolo1, Maria Teresa Di Martino1, Mariamena Arbitrio2, Antonio Giordano3,4, Pierosandro Tagliaferri1, Pierfrancesco Tassone1,4
1Department of Experimental and Clinical Medicine and T. Campanella Cancer Center, Magna Graecia University, S. Venuta University Campus, Catanzaro, Italy
2ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy
3Department of Human Pathology and Oncology, University of Siena, Siena, Italy
4Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
Pierfrancesco Tassone, e-mail: [email protected]
Keywords: miR-21, miRNAs, multiple myeloma bone disease, OPG, RANKL
Received: May 05, 2015 Accepted: June 11, 2015 Published: June 24, 2015
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.
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