MicroRNA-146a Regulates Human Foetal Femur Derived Skeletal Stem Cell Differentiation by Down-Regulating SMAD2 and SMAD3

Cheung, Kelvin; Sposito, Nunzia; Stumpf, Patrick S.; Wilson, David I.; Sánchez-Elsner, Tilman; Oreffo, Richard O.C.

doi:10.1371/journal.pone.0098063

Cited by 48 publications

(46 citation statements)

References 43 publications

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“…For example, miR-146a was found to be expressed by human fetal femur diaphyseal cells at a significantly higher level compared to epiphyseal populations. Detection of miR146a function in fetal femur cells confirmed regulation of protein translation of SMAD2 and SMAD3, resulting in a down-regulation of the chondrogenesis related gene SOX9 and up-regulation of the osteogenesis related gene RUNX2 [20].…”

Section: Introductionmentioning

confidence: 83%

MicroRNA-663 activates the canonical Wnt signaling through the adenomatous polyposis coli suppression

Miao¹,

Wei-jing²,

Xiong³

et al. 2015

Immunology Letters

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Section: Introductionmentioning

confidence: 83%

MicroRNA-663 activates the canonical Wnt signaling through the adenomatous polyposis coli suppression

Miao¹,

Wei-jing²,

Xiong³

et al. 2015

Immunology Letters

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“…23,26,27 Only a few miRNAs have been found to promote osteogenic differentiation. 25,42,43 In this study, we first identified miR-216a as an important enhancer of osteoblast differentiation of hAMSCs and hucMSCs. In the case of bone formation, MSCs generate new osteoblasts and their progenitors, which are essential for bone homeostasis and fracture healing.…”

Section: Discussionmentioning

confidence: 98%

miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway

Li¹,

Li²,

Fan³

et al. 2015

Cell Death Differ

117

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Osteoporosis is a disease marked by reduced bone mass, leading to an increased risk of fractures or broken bones. Bone formation is mediated by recruiting mesenchymal stem cells (MSCs). Elucidation of the molecular mechanisms that regulate MSC differentiation into osteoblasts is of great importance for the development of anabolic therapies for osteoporosis and other bone metabolism-related diseases. microRNAs (miRNAs) have been reported to have crucial roles in bone development, osteogenic differentiation and osteoporosis pathophysiology. However, to date, only a few miRNAs have been reported to enhance osteogenesis and regulate the suppressive effect of glucocorticoids on osteogenic differentiation. In this study, we discovered that miR-216a, a pancreatic-specific miRNA, was significantly upregulated during osteogenic differentiation in human adiposederived MSCs (hAMSCs). The expression of miR-216a was positively correlated with the expression of bone formation marker genes in clinical osteoporosis samples. Functional analysis demonstrated that miR-216a can markedly promote osteogenic differentiation of hAMSCs, rescue the suppressive effect of dexamethasone (DEX) on osteogenic differentiation in vitro and enhance bone formation in vivo. c-Cbl, a gene that encodes a RING finger E3 ubiquitin ligase, was identified as a direct target of miR-216a. Downregulation of c-Cbl by short hairpin RNAs can mimic the promotion effects of miR-216a and significantly rescue the suppressive effects of DEX on osteogenesis. Pathway analysis indicated that miR-216a regulation of osteogenic differentiation occurs via the c-Cbl-mediated phosphatidylinositol 3 kinase (PI3K)/AKT pathway. The recovery effects of miR-216a on the inhibition of osteogenesis by DEX were attenuated after blocking the PI3K pathway. Thus, our findings suggest that miR-216a may serve as a novel therapeutic agent for the prevention and treatment of osteoporosis and other bone metabolism-related diseases.

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“…Overexpression of miR‐483 in hMSCs reduced the expression of chondrogenic markers and GAGs production and this effect was shown to be achieved via direct targeting of SMAD4 . miR‐199a* and miR ‐ 146a exert anti‐chondrogenic roles by targeting SMAD1 and SMAD2/3, respectively . Pro‐chondrogenic growth factors other than TGF‐β were also shown to be regulated by miRNAs.…”

Section: Intracellular Anti‐chondrogenic Regulatorsmentioning

confidence: 99%

Targeting anti‐chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair

Lolli

Colella

Bari

et al. 2018

Journal Orthopaedic Research

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Trauma and age-related cartilage disorders represent a major global cause of morbidity, resulting in chronic pain and disability in patients. A lack of effective therapies, together with a rapidly aging population, creates an impressive clinical and economic burden on healthcare systems. In this scenario, experimental therapies based on transplantation or in situ stimulation of skeletal Mesenchymal Stem/progenitor Cells (MSCs) have raised great interest for cartilage repair. Nevertheless, the challenge of guiding MSC differentiation and preventing cartilage hypertrophy and calcification still needs to be overcome. While research has mostly focused on the stimulation of cartilage anabolism using growth factors, several issues remain unresolved prompting the field to search for novel solutions. Recently, inhibition of anti-chondrogenic regulators has emerged as an intriguing opportunity. Anti-chondrogenic regulators include extracellular proteins as well as intracellular transcription factors and microRNAs that act as potent inhibitors of pro-chondrogenic signals. Suppression of these inhibitors can enhance MSC chondrogenesis and production of cartilage matrix. We here review the current knowledge concerning different types of anti-chondrogenic regulators. We aim to highlight novel therapeutic targets for cartilage repair and discuss suitable tools for suppressing their anti-chondrogenic functions. Further effort is needed to unveil the therapeutic perspectives of this approach and pave the way for effective treatment of cartilage injuries in patients. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

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MicroRNA-146a Regulates Human Foetal Femur Derived Skeletal Stem Cell Differentiation by Down-Regulating SMAD2 and SMAD3

Cited by 48 publications

References 43 publications

MicroRNA-663 activates the canonical Wnt signaling through the adenomatous polyposis coli suppression

MicroRNA-663 activates the canonical Wnt signaling through the adenomatous polyposis coli suppression

miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway

Targeting anti‐chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair

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