title: miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease.
abstract: Skeletal homeostasis relies upon a fine tuning of osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-dependent bone formation. This balance is unsettled by multiple myeloma (MM) cells, which impair OBL function and stimulate OCLs to generate lytic lesions. Emerging experimental evidence is disclosing a key regulatory role of microRNAs (miRNAs) in the regulation of bone homeostasis suggesting the miRNA network as potential novel target for the treatment of MM-related bone disease (BD). Here, we report that miR-29b expression decreases progressively during human OCL differentiation in vitro. We found that lentiviral transduction of miR-29b into OCLs, even in the presence of MM cells, significantly impairs tartrate acid phosphatase (TRAcP) expression, lacunae generation, and collagen degradation, which are relevant hallmarks of OCL activity. Accordingly, expression of cathepsin K and metalloproteinase 9 (MMP9) as well as actin ring rearrangement were impaired in the presence of miR-29b. Moreover, we found that canonical targets C-FOS and metalloproteinase 2 are suppressed by constitutive miR-29b expression which also downregulated the master OCL transcription factor, NAFTc-1. Overall, these data indicate that enforced expression of miR-29b impairs OCL differentiation and overcomes OCL activation triggered by MM cells, providing a rationale for miR-29b-based treatment of MM-related BD.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Tommaso Campanella Cancer Center, Catanzaro, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rossi
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Pitari
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.forename: Francesco
authors.initials: F
authors.lastname: Conforti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leone
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.forename: Francesco Maria
authors.initials: FM
authors.lastname: Paolino
authors.forename: Teresa
authors.initials: T
authors.lastname: Del Giudice
authors.forename: Eleonora
authors.initials: E
authors.lastname: Iuliano
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D001862:Bone Resorption / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D015870:Gene Expression; D016762:Genes, fos; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism* / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D010014:Osteolysis / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D000199:Actins; D024042:Collagen Type I; D007527:Isoenzymes; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C534130:CTSK protein, human; D056657:Cathepsin K; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9