MicroRNA‐29a Protects Against Glucocorticoid‐Induced Bone Loss and Fragility in Rats by Orchestrating Bone Acquisition and Resorption

Wang, Feng‐Sheng; Chuang, Pei-Chin; Lin, Chin‐An; Chen, Mingwen; Ke, Huei-Ching; Chang, Yu‐Hsuan; Chen, Yu‐Shan; Wu, Shin-Long; Ko, Jih‐Yang

doi:10.1002/art.37948

Cited by 107 publications

(94 citation statements)

References 49 publications

(59 reference statements)

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“…So far only miR-29a has been reported to ameliorate glucocorticoid-induced suppression of osteoblast differentiation by regulating Wnt/β-catenin pathway. 33,34 In this study, we found that overexpression of miR-216a can significantly rescue the suppressive effects of DEX on the osteoblast differentiation of hAMSCs, which suggested that therapeutic upregulation of miR-216a in MSCs may promote bone formation and even reverse osteoporosis. With the development of miRNA delivery system, which can Damage of the bone formation potential of MSCs is responsible for the bone loss incurred in aging and osteoporosis.…”

Section: Discussionmentioning

confidence: 60%

“…[30][31][32] However, to date, only a few miRNAs have been reported to be antagonists for the suppression of glucocorticoids during osteogenic differentiation. 33,34 In this study, we revealed that miR-216a promotes the osteogenic differentiation of human adipose-derived MSCs (hAMSCs) in vitro and enhances bone formation in vivo. Moreover, we demonstrated that a high concentration of dexamethasone (DEX) inhibits osteogenic differentiation, whereas miR-216a antagonizes the suppressive effect of DEX on osteogenic differentiation.…”

mentioning

confidence: 96%

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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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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 96%

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

View full text Add to dashboard Cite

show abstract

“…Interestingly, miR-29a, which had been previously shown to suppress Osteonectin during osteoblastogenesis, 36 was found to protect against glucocorticoid-induced bone loss, a frequent pathological repercussion that leads to decreased osteoblast survival and increased osteoclast activity. 37 Forced expression of miR-29a attenuated the effects of glucocorticoid treatment, increasing trabecular bone mass and decreasing cortical bone porosity.…”

Section: Mirna Regulation Of Other Bone-related Pathologiesmentioning

confidence: 99%

MicroRNAs as regulators of bone homeostasis and bone metastasis

Ell

Kang

2014

Bonekey Reports

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MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.BoneKEy Reports 3, Article number: 549 (2014) | doi:10.1038/bonekey.2014.44 MiRNA Biogenesis and FunctionThe past decade has seen a torrent of novel research into the post-translational regulation of genes via microRNA-mediated suppression. The microRNAs (miRNAs) are a class of B22-nucleotide-long RNAs that repress gene expression through complementary binding to sites in the 3 0 -untranslated region (UTR) of target mRNAs. 1 Mature miRNAs are generated by the sequential cleavage of longer precursor transcripts, or pri-miRNAs, that are typically transcribed from intragenic or intergenic regions by RNA polymerase II. 2 The initial cleavage step, mediated by Drosha and the DGCR8 complex, occurs in the nucleus and produces a shortened (70-100 nucleotides) pre-miRNA hairpin. Pre-miRNAs are exported from the nucleus by Exportin 5, followed by a second cleavage by the ribonuclease Dicer that produces a double-stranded, B18-25-nucleotide-long mature miRNA. One miRNA strand will then combine with Argonaute (AGO2) proteins to produce an RNAinduced silencing complex, allowing for directed pairing with target mRNAs. 1

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“…For example, a reduction in miRNA-29a expression, which interacts with Wnt signalling components and Dkk-1 during osteoblast differentiation was associated with GC-associated bone loss. Gain of miRNA-29a function by a miRNA-29a precursor (Wang et al 2013) attenuated the deleterious effects of GC treatment on bone mass, microarchitecture and biomechanical strength.…”

Section: Gcs and Their Mechanisms Gc-induced Osteoporosismentioning

confidence: 99%

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

Wood

Souček

Wong

et al. 2018

Journal of Endocrinology

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Glucocorticoids (GCs) are effective for the treatment of many chronic conditions, but their use is associated with frequent and wide-ranging adverse effects including osteoporosis and growth retardation. The mechanisms that underlie the undesirable effects of GCs on skeletal development are unclear, and there is no proven effective treatment to combat them. An in vivo model that investigates the development and progression of GC-induced changes in bone is, therefore, important and a wellcharacterized pre-clinical model is vital for the evaluation of new interventions. Currently, there is no established animal model to investigate GC effects on skeletal development and there are pros and cons to consider with the different protocols used to induce osteoporosis and growth retardation. This review will summarize the literature and highlight the models and techniques employed in experimental studies to date.

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MicroRNA‐29a Protects Against Glucocorticoid‐Induced Bone Loss and Fragility in Rats by Orchestrating Bone Acquisition and Resorption

Abstract: MicroRNA-29a signaling protected against glucocorticoid-induced disturbance of Wnt and Dkk-1 actions and improved osteoblast differentiation and mineral acquisition. Promotion of miR-29a signaling is an alternative strategy for alleviating glucocorticoid-induced bone deterioration.

Cited by 107 publications

References 49 publications

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

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

MicroRNAs as regulators of bone homeostasis and bone metastasis

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

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