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

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

doi:10.18632/oncotarget.4398

Cited by 87 publications

(74 citation statements)

References 64 publications

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“…A variety of studies have to date demonstrated the potential relevance of miRNA mimics/inhibitors as therapeutic tools, and the promising results from the first Phase-2 trial in patients with HCV infection treated with Locked Nucleic Acid (LNA)-miR-122 inhibitors have further stimulated studies for the treatment of human cancer (16). In MM, miRNA-based strategies are presently emerging as promising approaches (17–25). Moreover, recent findings have emphasized the role of miRNAs in the development of drug-resistance in a variety of malignancies (26).…”

Section: Introductionmentioning

confidence: 99%

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

Gullà

Martino

Cantafio

et al. 2016

Clinical Cancer Research

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105

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Purpose The onset of drug-resistance is a major cause of treatment failure in multiple myeloma (MM). While increasing evidence is defining the role of microRNAs in mediating drug-resistance, their potential activity as drug-sensitizing agents has not yet been investigated in MM. Experimental Design Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory MM cells to melphalan. Results MiR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice. Conclusions Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan-resistance in preclinical models of MM, providing the framework for clinical trials to overcome drug resistance and improve patient outcome in MM.

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Section: Introductionmentioning

confidence: 99%

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

Gullà

Martino

Cantafio

et al. 2016

Clinical Cancer Research

Self Cite

105

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“…In the bone metastasis, bone damage is not directly caused by cancer/stromal cells but by the receptor activator of nuclear factor κ-B ligand (RANKL) activated by them. The activation of RANKL enhances the binding activity between RANKL and RANK (its receptor), leading to expression of osteoclasts [4, 35]. Aditi Gupta et al reported that, the expression of RANKL could be knocked down by phosphorylation of Smad5 suppression, therefore reducing osteoclast differentiation and consequently lessening bone loss and BCP [36].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Xiao

Lou

et al. 2016

Oncotarget

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ObjectiveIn this study, we aim to find out the role of microRNA-93-5p (miR-93) and Smad5 in morphine tolerance in mouse models of bone cancer pain (BCP).ResultsAt 7 days after injection of morphine, the PMWT showed no significant difference between the morphine model group and the saline model group (P < 0.05), suggesting that morphine tolerance had formed in the morphine model group. The morphine model group had higher miR-93 expression and lower Smad5 mRNA expression than the saline model group. Smad5 is a downstream target gene of miR-93. At 7, 9 and 14 days after injection of lentiviruses, the L/anti-miR-93 group had the lowest PMWTs, while the Smad5 shRNA group presented the highest PMWTs among these five groups (all P < 0.05).MethodsWe built mouse models of BCP and morphine tolerance and recorded 50% PMWT. After 6 days of modeling, we set saline control group, morphine control, saline model group and morphine model group (morphine tolerance emerged). We performed luciferase reporter gene assay to verify the relation between miR-93 and Smad5. After lentivirus transfection, the mice with morphine tolerance were assigned into L/anti-miR-93 group, Smad5 shRNA group, L/anti-miR-93 + Smad5 shRNA group, blank group and PBS control group. RT-qPCR, Western Blot assay and immumohistochemical staining were performed to observe the changes of miR-93 and Smad5.ConclusionUp-regulation of miR-93 may contribute to the progression of morphine tolerance by targeting Smad5 in mouse model of BCP.

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“…The maturation and formation of osteoclasts is primarily regulated by the balance of extracellular OPG and RANKL (26). OPG and RANKL cytokines affect the activity of osteoblast cells and osteoclastogenesis (26).…”

Section: Hcd Supplementation Regulates the Opg/rankl Ratiomentioning

confidence: 99%

“…OPG and RANKL cytokines affect the activity of osteoblast cells and osteoclastogenesis (26). OPG cytokine binds to RANKL and prevents RANKL from binding to the RANK receptor on osteoclast cells, subsequently inhibiting bone resorption and osteoclastogenesis (27).…”

Section: Hcd Supplementation Regulates the Opg/rankl Ratiomentioning

confidence: 99%

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

et al. 2018

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Abstract. Dietary calcium (Ca) supplementation has beneficial effects on bone health. However, it is not clear whether a high calcium diet (HCD) following 5/6 nephrectomy (5/6 Nx) is beneficial to bone health. The aim of the present study was to examine the effects of an HCD on bone metabolism using a chronic kidney disease (CKD) mouse model. Male C57BL/6J mice were divided into three groups: Sham group, 5/6 Nx group and 5/6 Nx + HCD group. Mice were sacrificed 12 weeks post-surgery. Calcium (Ca) and creatinine (Cr) were measured using standard colorimetric methods and picric acid methods, respectively. Bone metabolism-associated markers, FGF-23, PTH, ALP-b and TRAP-5b were measured using ELISA kits. Lumbar vertebrae histomorphological analysis was performed using hematoxylin and eosin staining. The expression of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) mRNA was detected using reverse transcription-quantitative polymerase chain reaction. Impaired renal function and histopathological damage was indicated in 5/6 Nx mice. However, HCD had no significant effects on these changes in 5/6 Nx mice. Notably, mineral metabolism disorder and histopathological damage to lumbar vertebrae were markedly improved in HCD-treated 5/6 Nx mice. Compared with 5/6 Nx mice, HCD supplementation significantly elevated the ratio of OPG/RANKL and inhibited RANKL mRNA expression in lumbar vertebrae. To conclude, the present findings indicated that increased Ca intake is effective in increasing bone mineral content of the lumbar vertebrae in 5/6 Nx mice. These results may provide a basis for the clinical use of dietary Ca supplementation as a therapeutic approach to treat CKD-induced disturbance of mineral metabolism and bone loss.

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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

Cited by 87 publications

References 64 publications

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

High calcium diet alleviates 5/6 nephrectomy-induced bone deteriorations of lumbar vertebrae in mice

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