Circulating microRNAs Correlate with Multiple Myeloma and Skeletal Osteolytic Lesions

Moura, Sara Reis; Abreu, Hugo; Cunha, Carla; Ribeiro-Machado, Cláudia; Oliveíra, Carla; Barbosa, Mário A.; Marques, Herlander; Almeida, Maria Inês

doi:10.3390/cancers13215258

Cited by 11 publications

(7 citation statements)

References 44 publications

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“…Furthermore, we showed that the H19 expression is regulated by miR-29c-3p, whose levels are decreased in bone samples from osteoporotic patients, and that it negatively changes COL1 expression, which is in agreement with previous studies [59,60]. In a recent study published by our group, miR-29c-3p was identified as a marker of secondary osteoporosis in multiple myeloma plasma samples [61]. Modulation of miR-29c-3p affects MSC proliferative capacity, without impacting cell death or osteogenic differentiation and mineralization in the early stages of differentiation.…”

Section: Discussionsupporting

confidence: 92%

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

et al. 2023

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Background The vast and promising class of long non-coding RNAs (lncRNAs) has been under investigation for distinct therapeutic applications. Nevertheless, their role as molecular drivers of bone regeneration remains poorly studied. The lncRNA H19 mediates osteogenic differentiation of Mesenchymal Stem/Stromal Cells (MSCs) through the control of intracellular pathways. However, the effect of H19 on the extracellular matrix (ECM) components is still largely unknown. This research study was designed to decode the H19-mediated ECM regulatory network, and to reveal how the decellularized siH19-engineered matrices influence MSC proliferation and fate. This is particularly relevant for diseases in which the ECM regulation and remodeling processes are disrupted, such as osteoporosis. Methods Mass spectrometry-based quantitative proteomics analysis was used to identify ECM components, after oligonucleotides delivery to osteoporosis-derived hMSCs. Moreover, qRT-PCR, immunofluorescence and proliferation, differentiation and apoptosis assays were performed. Engineered matrices were decellularized, characterized by atomic force microscopy and repopulated with hMSC and pre-adipocytes. Clinical bone samples were characterized by histomorphometry analysis. Results Our study provides an in-depth proteome-wide and matrisome-specific analysis of the ECM proteins controlled by the lncRNA H19. Using bone marrow-isolated MSC from patients with osteoporosis, we identified fibrillin-1 (FBN1), vitronectin (VTN) and collagen triple helix repeat containing 1 (CTHRC1), among others, as having different pattern levels following H19 silencing. Decellularized siH19-engineered matrices are less dense and have a decreased collagen content compared with control matrices. Repopulation with naïve MSCs promotes a shift towards the adipogenic lineage in detriment of the osteogenic lineage and inhibits proliferation. In pre-adipocytes, these siH19-matrices enhance lipid droplets formation. Mechanistically, H19 is targeted by miR-29c, whose expression is decreased in osteoporotic bone clinical samples. Accordingly, miR-29c impacts MSC proliferation and collagen production, but does not influence ALP staining or mineralization, revealing that H19 silencing and miR-29c mimics have complementary but not overlapping functions. Conclusion Our data suggest H19 as a therapeutic target to engineer the bone ECM and to control cell behavior.

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Section: Discussionsupporting

confidence: 92%

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

et al. 2023

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“…miR-21 serum levels at relapse were associated with ISS stage. From previous studies, plasma levels of miRNA 16 were associated with B2M [ 24 ], ISS disease stage and PFS in myeloma [ 18 ]. In addition, serum miR-21 was significantly different according to the Durie and Salmon stages, correlating with B2M, IgG, and albumin levels [ 19 ]…”

Section: Discussionmentioning

confidence: 99%

Circulating miR-16 and miR-21 Levels in Multiple Myeloma: Prognostic Significance of Survival and Response to Lenalidomide Treatment

Gkioka,

Tsota,

Koudouna

et al. 2024

IJMS

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MicroRNAs (miRNAs), particularly miR-16 and miR-21, play a crucial role in multiple myeloma (MM) pathogenesis by regulating gene expression. This study evaluated the prognostic significance of circulating miR-16 and miR-21 expression levels in 48 patients with MM at diagnosis treated with lenalidomide–dexamethasone (LD) compared with 15 healthy individuals (HI). All patients were treated with LD, 13 at first line and 35 at relapse, of whom 21 were tested twice at diagnosis and before LD initiation. The results revealed significantly lower levels of miR-16 and miR-21 in patients than in HIs, both at diagnosis and relapse, with decreased miR-16 levels at diagnosis, indicating improved overall survival (OS) (p value 0.024). Furthermore, miR-16 and miR-21 levels were associated with disease markers, while both correlated with the depth of response and mir-16 with sustained response to LD treatment. Ratios of both miR-16 and miR-21 expression levels (prior to LD treatment/diagnosis) below two predicted a shorter time to response (p = 0.027) and a longer time to next treatment (p = 0.042), respectively. These findings suggested a prognostic value for serum miR-16 and miR-21 levels in MM, as their expression levels correlated with disease variables and treatment outcomes.

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“…Also, we showed H19 expression is regulated by miR-29c-3p, which levels are decreased in bone samples from osteoporotic patients, and that negatively changes COL I expression, which is in agreement with previous studies 49,50 . In a recent study published by our group, miR-29c-3p was identi ed as a marker of secondary osteoporosis in multiple myeloma plasma samples 51 . Modulation of miR-29c-3p affects MSC proliferative capacity, without changing cell death or osteogenic differentiation and mineralization in early stages of differentiation.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

Moura

Freitas

Ribeiro-Machado

et al. 2022

Preprint

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BackgroundProteins, protein-encoding transcripts and microRNAs have been investigated as molecular drivers of bone regeneration but few reached clinical relevance, while the vast and promising class of long non-coding RNAs (lncRNAs) remains poorly studied. The lncRNA H19 mediates osteogenic differentiation of Mesenchymal Stem/Stromal Cells (MSCs) through the control of intracellular pathways. However, the effect of H19 over the extracellular matrix (ECM) components remains largely unknown. This study was designed to decode the H19-mediated ECM regulatory network and to reveal how the decellularized siH19-engineered matrices influence MSC proliferation and fate. This is particularly relevant for diseases in which the ECM regulation and remodelling processes are disrupted, such as in osteoporosis.MethodsMass spectrometry-based quantitative proteomics analysis was used to identify ECM components, after oligonucleotides delivery to osteoporosis-derived hMSCs. qRT-PCR, immunofluorescence and proliferation, differentiation, apoptosis assays were performed. Engineered matrices were decellularized, characterized by atomic force microscopy and repopulated with hMSC and pre-adipocytes. Clinical bone samples were characterized by histomorphometry analysis. ResultsOur study provides an in-depth proteome-wide and matrisome-specific analysis of the ECM proteins controlled by the lncRNA H19. Using bone-marrow isolated MSC from osteoporosis patients, we identified fibrillin-1 (FBN1), vitronectin (VTN) and collagen triple helix repeat containing 1 (CTHRC1), among others, as having different pattern levels following H19 silencing. Decellularized siH19-engineered matrices are less dense and with a decreased collagen content compared with control matrices. Repopulation with naïve MSCs promotes a shift towards the adipogenic lineage in detriment of the osteogenic lineage and inhibits proliferation. In pre-adipocytes, these siH19-matrices enhance lipid droplets formation. Mechanistically, H19 is targeted by miR-29c, which expression is decreased in osteoporotic bone clinical samples. Accordingly, miR-29c impacts MSC proliferation and collagen production, but do not influence ALP staining or mineralization, revealing H19 silencing and miR-29c mimics have complementary but not overlapping functions.ConclusionOur data suggests H19 as a therapeutic target to engineer the bone ECM and control cell behaviour.

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Circulating microRNAs Correlate with Multiple Myeloma and Skeletal Osteolytic Lesions

Cited by 11 publications

References 44 publications

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

Circulating miR-16 and miR-21 Levels in Multiple Myeloma: Prognostic Significance of Survival and Response to Lenalidomide Treatment

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

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