bims-mirbon 2021-10-24 papers

bims-mirbon

Biomed News

on MicroRNAs in Bone

Issue of 2021‒10‒24
seven papers selected by
Japneet Kaur
Mayo Clinic

miR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2.
MicroRNA-15a-5p plays a role in osteogenic MC3T3-E1 cells differentiation by targeting PDCD4 (programmed cell death 4) via Wnt/β-catenin dependent signaling pathway.
Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway.
Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1.
Role of MiR-325-3p in the Regulation of CFL2 and Myogenic Differentiation of C2C12 Myoblasts.
BMSC-Derived Exosomes Inhibit Dexamethasone-Induced Muscle Atrophy via the miR-486-5p/FoxO1 Axis.
Expression Profile Analysis of Long Non-coding RNA in OVX Models-Derived BMSCs for Postmenopausal Osteoporosis by RNA Sequencing and Bioinformatics.

Int J Mol Sci. 2021 Oct 12. pii: 10988. [Epub ahead of print]22(20):

miR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2.

Ya-Li Zhang, Liang Liu, Yu-Wen Su, Cory J Xian.

  Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and miR-542-3p was recently shown to regulate osteogenesis in a bone loss context, the role of miR-542-3p in regulating osteogenesis and adipogenesis balance is not clear. Herein, in a rat MTX treatment-induced bone loss model, miR-542-3p was found significantly downregulated during the period of bone loss and marrow adiposity. Following target prediction, network construction, and functional annotation/ enrichment analyses, luciferase assays confirmed sFRP-1 and Smurf2 as the direct targets of miR-542-3p. miRNA-542-3p overexpression suppressed sFRP-1 and Smurf2 expression post-transcriptionally. Using in vitro models, miR-542-3p treatment stimulated osteogenesis but attenuated adipogenesis following MTX treatment. Subsequent signalling analyses revealed that miR-542-3p influences Wnt/β-catenin and TGF-β signalling pathways in osteoblastic cells. Our findings suggest that MTX treatment-induced bone loss and marrow adiposity could be molecularly linked to miR-542-3p pathways. Our results also indicate that miR-542-3p might be a therapeutic target for preserving bone and attenuating marrow fat formation during/after MTX chemotherapy.

Keywords:  bone formation; marrow adiposity; methotrexate; miRNA-542-3p

DOI:  https://doi.org/10.3390/ijms222010988
Bioengineered. 2021 Dec;12(1): 8173-8185

MicroRNA-15a-5p plays a role in osteogenic MC3T3-E1 cells differentiation by targeting PDCD4 (programmed cell death 4) via Wnt/β-catenin dependent signaling pathway.

Qiang Wang, Yiming Miao, Zhiyuan Qian, Lidong Chen, Tong Lu, Yue Xu, Xiaowei Jiang, Yingchao Shen.

  Osteoporosis is defined as a bone condition characterized by bone mass reduction, bone micro-architectural and quality deterioration, leading to compromised strength and increased chances of fracture. Evidence have shown an essential role of microRNAs (miRNAs) in various osteogenic differentiation processes. However, the function of miR-15a-5p in the differentiation of osteogenic cells and possible mechanisms remains unclear. The present study explored the expression of miR-15a-5p in human osteoporosis specimens and during the osteogenic differentiation of MC3T3-E1 cells. Functions of miR-15a-5p were determined using miR-15a-5p mimics and inhibitors. Luciferase assay was used to verify the binding of miR-15a-5p and PDCD4 3'UTR. Alizarin Red Staining (ARS) and Alkaline phosphatase (ALP) activity were used to determine the miR-15a-5p role in osteogenic differentiation. Finally, Wnt pathway inhibitor was used to determine the miR-15a-5p/PDCD4/Wnt signaling pathway in regulating osteogenic differentiation. We found miR-15a-5p expression was increased in human osteoporosis specimens and during differentiation of MC3T3-E1 cells. PDCD4 was also identified as a target of miR-15a-5p and was found to be involved in osteogenic differentiation. Further, miR-15a-5p mimics attenuated the effects of PDCD4 overexpression. Finally, use of XAV939 (Wnt pathway inhibitor) downregulated osteogenic differentiation in miR-15a5p/PDCD4/Wnt-dependent signaling pathway. In conclusion, miR-15a-5p induced differentiation of osteoblasts and mineralization by modulating osteoblast differentiation factors, mainly OSX, ALP, OCN, and RUNX2, by inhibiting PDCD4 and Wnt signaling pathways. This study provides a modality for the future use of miR-15a-5p in the treatment and prevention of osteoporosis.

Keywords:  Wnt/β-catenin pathway; miR-15a-5p; osteoporosis; programmed cell death 4 (PDCD4)

DOI:  https://doi.org/10.1080/21655979.2021.1977766
Inflammation. 2021 Oct 21.

Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway.

Yan Wang, Xiaoqi Zhou, Dalin Wang.

  Osteoporosis (OP) is a systemic skeletal disease that promotes bone fragility and the risk of fractures. Recent studies have shown the relevance of microRNAs (miRNAs) in the development of OP. This study aimed to evaluate the possible mechanisms of action underlying miR-27a loaded by mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in OP. Serum samples from OP patients and normal controls were collected for miRNA microarray analysis. The expression of filtered miRNA was upregulated in osteoblasts (OB) and osteoclasts (OCs) for biological activity assessment. After developing OP mice using ovariectomy (OVX) and confirming OP, the miR-27a expression level was upregulated in mice by MSC-EV application. Dual-luciferase assays were conducted to validate the relationship between miR-27a and DKK2 expression. The poor expression of miR-27a was observed in patients with OP. miR-27a increased the expression of OB markers, the number of ALP-positive cells, and the number of calcium nodules in OCs. In OVX mice, miR-27a increased bone density, improved bone structure damage recovery, decreased the levels of bone resorption markers, and decreased OC number. miR-27a transmitted by MSC-EVs interacted with DKK2. MSC-EVs exerted the same protective effects as miR-27a on OP, whereas miR-27a inhibitor abolished the attenuating effects of MSC-EVs. In contrast, DKK2 depletion reversed the stimulatory effects of the miR-27a inhibitor on OP. The Wnt/β-catenin pathway was activated upon MSC-EV application and DKK2 silencing and was impaired upon the downregulation of the expression of miR-27a. MSC-EVs are effective in preventing mouse OP. This mechanism is mediated by the miR-27a/DKK2/Wnt/β-catenin signaling pathway.

Keywords:  DKK2; Wnt/β-catenin pathway; mesenchymal stem cell–derived extracellular vesicles; microRNA-27a; osteoporosis.

DOI:  https://doi.org/10.1007/s10753-021-01583-z
Metabolism. 2021 Oct 16. pii: S0026-0495(21)00216-X. [Epub ahead of print] 154916

Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1.

Yudan Zhang, Yingying Cai, Hongbin Zhang, Jiajun Zhang, Yanmei Zeng, Cunxia Fan, Shaozhou Zou, Chunyan Wu, Shu Fang, Ping Li, Xiaochun Lin, Ling Wang, Meiping Guan.

  OBJECTIVE: Adipose tissue is a major source of circulating microRNAs (miRNAs) that can regulate target genes in distant organs. However, the role of brown adipose tissue (BAT) in diabetic kidney disease (DKD) is still unknown. We studied the original BAT miR-30b targeting two key fibrotic regulators, Runt-related transcription factor 1 (Runx1) and snail family zinc finger 1 (Snail1), to combat DKD.METHODS: First, we transplanted healthy BAT from normal mouse donors into diabetic mice (induced by a high-fat diet and streptozotocin injection). In vitro, we observed extracellular vesicles (EVs) secreted from brown adipocytes. AgomiR-30b was directly administered to the BAT of diabetic mice twice weekly for 4 consecutive weeks. Next, the role of Runx1 in DKD was determined by using siRUNX1 or pCMV-RUNX1 in HK-2 cells and in diabetic mice treated with AAV9-U6-shRunx1 or AAV9-EF1a-Runx1.
RESULTS: BAT transplantation reactivated endogenous BAT activity in diabetic mice, increased circulating miR-30b levels and significantly ameliorated DKD. In TGFβ1-treated HK-2 cells, miR-30b expression was significantly suppressed. miR-30b overexpression markedly decreased fibronectin and downregulated Runx1 and Snail1 expression, while silencing of miR-30b had the opposite effects. Next, Runx1 knockdown and overexpression mimicked the above phenotype of miR-30b mimics and inhibitors, respectively, both in vitro and in vivo. Moreover, Runx1 promoted TGFβ1-induced fibrosis by upregulating the PI3K pathway.
CONCLUSION: BAT-derived miRNAs might be a promising target for kidney protection in diabetes mellitus.

Keywords:  Brown adipose tissue; Diabetic nephropathy; Runx1; Transplantation; miR-30b

DOI:  https://doi.org/10.1016/j.metabol.2021.154916
Cells. 2021 Oct 12. pii: 2725. [Epub ahead of print]10(10):

Role of MiR-325-3p in the Regulation of CFL2 and Myogenic Differentiation of C2C12 Myoblasts.

Mai Thi Nguyen, Wan Lee.

  Skeletal myogenesis is required to maintain muscle mass and integrity, and impaired myogenesis is causally linked to the etiology of muscle wasting. Recently, it was shown that excessive uptake of saturated fatty acids (SFA) plays a significant role in the pathogenesis of muscle wasting. Although microRNA (miRNA) is implicated in the regulation of myogenesis, the molecular mechanism whereby SFA-induced miRNAs impair myogenic differentiation remains largely unknown. Here, we investigated the regulatory roles of miR-325-3p on CFL2 expression and myogenic differentiation in C2C12 myoblasts. PA impeded myogenic differentiation, concomitantly suppressed CFL2 and induced miR-325-3p. Dual-luciferase analysis revealed that miR-325-3p directly targets the 3'UTR of CFL2, thereby suppressing the expression of CFL2, a crucial factor for actin dynamics. Transfection with miR-325-3p mimic resulted in the accumulation of actin filaments (F-actin) and nuclear Yes-associated protein (YAP) in myoblasts and promoted myoblast proliferation and cell cycle progression. Consequently, miR-325-3p mimic significantly attenuated the expressions of myogenic factors and thereby impaired the myogenic differentiation of myoblasts. The roles of miR-325-3p on CFL2 expression, F-actin modulation, and myogenic differentiation suggest a novel miRNA-mediated regulatory mechanism of myogenesis and PA-inducible miR-325-3p may be a critical mediator between obesity and muscle wasting.

Keywords:  CFL2; differentiation; miR-325-3p; microRNA; palmitic acid; proliferation

DOI:  https://doi.org/10.3390/cells10102725
Front Endocrinol (Lausanne). 2021 ;12 681267

BMSC-Derived Exosomes Inhibit Dexamethasone-Induced Muscle Atrophy via the miR-486-5p/FoxO1 Axis.

Ziyi Li, Chang Liu, Shilun Li, Ting Li, Yukun Li, Na Wang, Xiaoxue Bao, Peng Xue, Sijing Liu.

  Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging, injury, hormone imbalance and other catabolic conditions. Recently, exosomes were considered to regulate muscle regeneration and protein synthesis. In order to confirm the effect of BMSC-derived exosomes (BMSC-Exos) on muscle, dexamethasone-induced muscle atrophy was built both in vitro and in vivo. In the present research, BMSC-Exos attenuated the decrease of myotube diameter induced by dexamethasone, indicating that BMSC-Exos played a protective role in skeletal muscle atrophy. Further mechanism analysis exhibited that the content of miR-486-5p in C2C12 myotubes was up-regulated after treated with BMSC-Exos. Meanwhile, BMSC-Exos markedly downregulated the nuclear translocation of FoxO1, which plays an important role in muscle differentiation and atrophy. Importantly, the miR-486-5p inhibitor reversed the decreased expression of FoxO1 induced by BMSC-Exos. In animal experiments, BMSC-Exos inhibited dexamethasone-induced muscle atrophy, and miR-486-5p inhibitor reversed the protective effect of BMSC-Exos. These results indicating that BMSC-derived exosomes inhibit dexamethasone-induced muscle atrophy via miR486-5p/Foxo1 Axis.

Keywords:  FoxO1; bone marrow mesenchymal stem cell; exosomes; miR-486-5p; muscle atrophy

DOI:  https://doi.org/10.3389/fendo.2021.681267
Front Cell Dev Biol. 2021 ;9 719851

Expression Profile Analysis of Long Non-coding RNA in OVX Models-Derived BMSCs for Postmenopausal Osteoporosis by RNA Sequencing and Bioinformatics.

Huijie Gu, Zhongyue Huang, Kaifeng Zhou, Guangnan Chen, Chong Bian, Jun Xu, Xiaofan Yin.

  Osteoporosis (OP) has the characteristics of a systematically impaired bone mass, strength, and microstructure. Long non-coding RNAs (lncRNAs) are longer than 200 nt, and their functions in osteoporosis is yet not completely understood. We first harvested the bone marrow mesenchymal stem cells (BMSCs) from ovariectomy (OVX) and sham mice. Then, we systematically analyzed the differential expressions of lncRNAs and messenger RNAs (mRNAs) and constructed lncRNA-mRNA coexpression network in order to identify the function of lncRNA in osteoporosis. Totally, we screened 743 lncRNAs (461 upregulated lncRNAs and 282 downregulated lncRNAs) and 240 mRNAs (128 upregulated and 112 downregulated) with significantly differential expressions in OP compared to normal. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses to investigate the functions and pathways of the differential expression of messenger RNAs (mRNAs), a coexpressed network of lncRNA/mRNA. Quantitative PCR (qPCR) validated that the expressions of NONMMUT096150.1, NONMMUT083450.1, and NONMMUT029743.2 were all downregulated, whereas NONMMUT026970.2, NONMMUT051734.2, NONMMUT003617.2, and NONMMUT034049.2 were all upregulated in the OVX group. NONMMUT096150.1, as a key lncRNA in OP, was identified to modulate the adipogenesis of BMSCs. Further analysis suggested that NONMMUT096150.1 might modulate the adipogenesis of BMSCs via the peroxisome proliferator-activated receptor (PPAR) signaling pathway, AMPK signaling pathway, and the lipolysis regulation in adipocyte and adipocytokine signaling pathway. Our study expands the understanding of lncRNA in the pathogenesis of OP.

Keywords:  BMSCs; NONMMUT0961501; OVX model; differentially expressed; lncRNA; osteoporosis

DOI:  https://doi.org/10.3389/fcell.2021.719851