bims-mirbon 2021-10-31 papers

bims-mirbon

Biomed News

on MicroRNAs in bone

Issue of 2021–10–31
fourteen papers selected by
Japneet Kaur, Mayo Clinic

miR-452-3p inhibited osteoblast differentiation by targeting Smad4.
TP53-mediated miR-2861 promotes osteogenic differentiation of BMSCs by targeting Smad7.
miR-125a-5p-abundant exosomes derived from mesenchymal stem cells suppress chondrocyte degeneration via targeting E2F2 in traumatic osteoarthritis.
Exosomal microRNA-98-5p from hypoxic bone marrow mesenchymal stem cells inhibits myocardial ischemia-reperfusion injury by reducing TLR4 and activating the PI3K/Akt signaling pathway.
Update on Osteoporosis Screening and Management.
miR-19b-3p is associated with a diametric response to resistance exercise in older adults and regulates skeletal muscle anabolism via PTEN inhibition.
Plasma Exosome-Enriched Extracellular Vesicles From Lactating Mothers With Type 1 Diabetes Contain Aberrant Levels of miRNAs During the Postpartum Period.
Exploring the Extracellular Vesicle MicroRNA Expression Repertoire in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis Treated with TNF Inhibitors.
MiR-192-5p suppresses M1 macrophage polarization via epiregulin (EREG) downregulation in gouty arthritis.
Potential Roles of miRNA-1245a Regulatory Networks in Sarcopenia.
DCAF1-targeting microRNA-3175 activates Nrf2 signaling and inhibits dexamethasone-induced oxidative injury in human osteoblasts.
Exosomal miR-1275 Secreted by Prostate Cancer Cells Modulates Osteoblast Proliferation and Activity by Targeting the SIRT2/RUNX2 Cascade.
CircRFWD2 Promotes Osteogenic Differentiation of human Dental Pulp Stem Cells by Targeting miR-6817-5p Through BMP-Smad and p38 MAPK Pathway.
Long non-coding RNA NEAT1 and its targets (microRNA-21 and microRNA-125a) in rheumatoid arthritis: Altered expression and potential to monitor disease activity and treatment outcome.

PeerJ. 2021 ;9 e12228

miR-452-3p inhibited osteoblast differentiation by targeting Smad4.

Ming Wu, Hongyan Wang, Dece Kong, Jin Shao, Chao Song, Tieyi Yang, Yan Zhang.

  Osteoblast differentiation is a complex process that is essential for normal bone formation. A growing number of studies have shown that microRNAs (miRNAs) are key regulators in a variety of physiological and pathological processes, including osteogenesis. In this study, BMP2 was used to induce MC3T3-E1 cells to construct osteoblast differentiation cell model. Then, we investigated the effect of miR-452-3p on osteoblast differentiation and the related molecular mechanism by RT-PCR analysis, Western blot analysis, ALP activity, and Alizarin Red Staining. We found that miR-452-3p was significantly downregulated in osteoblast differentiation. Overexpression miR-452-3p (miR-452-3p mimic) significantly inhibited the expression of osteoblast marker genes RUNX2, osteopontin (OPN), and collagen type 1 a1 chain (Col1A1), and decreased the number of calcium nodules and ALP activity. In contrast, knockdown miR-452-3p (miR-452-3p inhibitor) produced the opposite effect. In terms of mechanism, we found that Smad4 may be the target of miR-452-3p, and knockdown Smad4 (si-Smad4) partially inhibited the osteoblast differentiation enhanced by miR-452-3p. Our results suggested that miR-452-3p plays an important role in osteoblast differentiation by targeting Smad4. Therefore, miR-452-3p is expected to be used in the treatment of bone formation and regeneration.

Keywords:  MC3T3-E1; Osteoblast differentiation; Osteoporosis; Smad4; miR-452-3p

DOI:  https://doi.org/10.7717/peerj.12228
Mol Cell Biochem. 2021 Oct 28.

TP53-mediated miR-2861 promotes osteogenic differentiation of BMSCs by targeting Smad7.

Xian-Pei Zhou, Qi-Wei Li, Zi-Zhen Shu, Yang Liu.

  Bone defect seriously affects the quality of life. Meanwhile, osteogenic differentiation in BMSCs could regulate the progression of bone defect. Transcription factors are known to regulate the osteogenic differentiation in BMSCs. The study aimed to investigate the detailed mechanism by which TP53 regulates the osteogenic differentiation. To study bone defect in vitro, BMSCs were isolated from spinal cord injury rats. CCK-8 assay was applied to test the cell viability. The mineralized nodules in BMSCs was tested by alizarin red staining. Meanwhile, TUNEL staining and flow cytometry were performed to test the cell apoptosis. mRNA expression was tested by qRT-PCR. Starbase and dual-luciferase reporter assay were used to predict the downstream mRNA of miR-2861. Moreover, western blot was applied to detect the protein expressions (TP53 and Smad7). BMSCs were successfully isolated from rats. The expressions of miR-2861 were significantly upregulated in osteogenic medium, compared with growth medium. MiR-2861 inhibitor significantly decreased the levels of OCN, ALP, BSP, and Runx2 in BMSCs. In addition, miR-2861 inhibitor notably inhibited the mineralized nodules, viability, and induced the apoptosis of BMSCs. Smad7 was identified to be the downstream target of miR-2861, and knockdown of Smad7 notably reversed miR-2861 inhibitor-induced inhibition of osteogenic differentiation and promotion of apoptosis in BMSCs. Moreover, miR-2861 was transcriptionally regulated by TP53 in BMSCs. TP53-meidiated miR-2861 promotes osteogenic differentiation of BMSCs by targeting Smad7. Thereby, our research might provide new methods for bone defect treatment.

Keywords:  BMSCs; Bone defect; Smad7; TP53; miR-2861

DOI:  https://doi.org/10.1007/s11010-021-04276-1
Bioengineered. 2021 Oct 28.

miR-125a-5p-abundant exosomes derived from mesenchymal stem cells suppress chondrocyte degeneration via targeting E2F2 in traumatic osteoarthritis.

Qingqing Xia, Quan Wang, Jie Li, Junjuan Wang.

  miRNAs are broad participants in vertebrate biological processes, and they are also the major players in pathological processes. miR-125a-5p was recently found a modulator in the progression of osteoarthritis (OA). Our study was aimed to explore the role and underlying mechanisms of miR-125a-5p-abundant exosomes derived from mesenchymal stem cells (MSC) on OA progression. We separated bone marrow mesenchymal stem cells (BMSCs) as well as the exosomes from traumatic OA patients. The immunofluorescence and cartilage staining were implemented for the observation and the assessment on endocytosis of chondrocytes and exosomal miR-125a-5p efficacy to cartilage degradation. Dual luciferase reporter assay was performed to verified the relationship between miR-125a-5p and E2F2. Then, the function of exosomal miR-125a-5p were examined on chondrocyte degeneration in vitro and in vivo. Our findings indicated that E2F2 expression was elevated while the miR-125a-5p was down in traumatic OA cartilage tissue, showing a negative correlation of the former and the latter. miR-125a-5p targets E2F2 in traumatic OA cartilage tissue and leads to the down-expression of E2F2. The E2F2 expression in chondrocytes was decreased after internalization of exosomes. We additionally found that BMSCs-derived exosomes were rich in miR-125a-5p content and chondrocytes can have it internalized. miR-125a-5p is endowed with a trait of accelerating chondrocytes migration, which is going along with the up-expressions of Collagen II, aggrecan and SOX9 and the down-expression of MMP-13 in vitro. Besides that, the mice model with post-traumatic OA turned out that exosomal miR-125a-5p might beget an alleviation in chondrocyte extracellular matrix degradation. All these outcomes revealed that BMSCs-derived exosomal miR-125a-5p is a positive regulator for chondrocyte migration and inhibit cartilage degeneration We thus were reasonable to believe that transferring of exosomal miR-125a-5p is a prospective strategy for OA treatment.

Keywords:  E2F2; bone marrow mesenchymal stem cells; chondrocyte degeneration; exosomes; miR-125a-5p; traumatic osteoarthritis

DOI:  https://doi.org/10.1080/21655979.2021.1995580
Int Immunopharmacol. 2021 Oct 26. pii: S1567-5769(21)00228-9. [Epub ahead of print]101(Pt B): 107592

Exosomal microRNA-98-5p from hypoxic bone marrow mesenchymal stem cells inhibits myocardial ischemia-reperfusion injury by reducing TLR4 and activating the PI3K/Akt signaling pathway.

Leiying Zhang, Qingxia Wei, Xiaomin Liu, Ting Zhang, Shuying Wang, Lingling Zhou, Liyang Zou, Fengyan Fan, Hongxu Chi, Jiayi Sun, Deqing Wang.

   OBJECTIVE: MicroRNAs (miRNAs) are essential biomarkers during development of human diseases. We aimed to explore the role of hypoxia-induced bone marrow mesenchymal stem cells (BMSCs)-derived exosomal miR-98-5p in myocardial ischemia-reperfusion injury (MI/RI).
METHODS: BMSCs were isolated, cultured, stimulated by hypoxia and transfected with adenovirus expressing miR-98-5p. The exosomes were extracted from BMSCs and named as BMSC-exos. The rat MI/RI models were established by ligation of left anterior descending artery and were respectively injected. Then, hemodynamic indices, myocardial enzymes, oxidative stress factors, inflammatory factors, macrophage infiltration and infarct size in these rats were determined. Expression of miR-98-5p, toll-like receptor 4 (TLR4) and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway-related proteins was assessed. The target relation between miR-98-5p and TLR4 was confirmed by bioinformatic method and dual luciferase report gene assay.
RESULTS: MiR-98-5p was downregulated, TLR4 was upregulated and the PI3K/Akt signaling pathway was inactivated in MI/RI rat myocardial tissues. Exosomal miR-98-5p from hypoxic BMSCs promoted cardiac function and suppressed myocardial enzyme levels, oxidative stress, inflammation response, macrophage infiltration and infarct size in I/R myocardial tissues. Moreover, TRL4 was targeted by miR-98-5p and miR-98-5p activated PI3K/Akt signaling pathway.
CONCLUSION: Hypoxia-induced BMSC-exos elevated miR-98-5p to protect against MI/RI. This study may be helpful for treatment of MI/RI.

Keywords:  Bone marrow mesenchymal stem cell; Exosome; MicroRNA-98-5p; Myocardial ischemia–reperfusion injury; Phosphatidylinositol-3-kinase/protein kinase B signaling pathway; Toll-like receptor 4

DOI:  https://doi.org/10.1016/j.intimp.2021.107592
Med Clin North Am. 2021 Nov;pii: S0025-7125(21)00085-7. [Epub ahead of print]105(6): 1117-1134

Update on Osteoporosis Screening and Management.

Anika K Anam, Karl Insogna.

  Osteoporosis is a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to an increased risk of fragility fractures. Central dual-energy X-ray absorptiometry measurements are the gold standard for determining bone mineral density. A well-balanced diet containing adequate amounts of calcium and vitamin D, exercise, smoking cessation, and limited alcohol intake are important to maintain bone health. Pharmacologic agents should be recommended in postmenopausal women who are at high risk for fractures. Newer anabolic therapies including teriparatide, abaloparatide, and romosozumab have emerged for use in severe osteoporosis.

Keywords:  Bone loss; Dual-energy X-ray absorptiometry; Fracture; Menopause; Osteoporosis

DOI:  https://doi.org/10.1016/j.mcna.2021.05.016
Am J Physiol Cell Physiol. 2021 Oct 27.

miR-19b-3p is associated with a diametric response to resistance exercise in older adults and regulates skeletal muscle anabolism via PTEN inhibition.

Donato A Rivas, Fei Peng, Townsend Benard, Adelino Sanchez Ramos da Silva, Roger A Fielding, Lee M Margolis.

  Our laboratory has discovered that dysregulation in microRNA (miRNA) that target anabolic signaling between younger and older adults is a potential molecular mechanism resulting in age-associated decreases in skeletal muscle mass and function (sarcopenia). Whether differences in miRNA expression profiles account for inter-individual variability in exercise adaptation in older adults is unclear. Understanding paradoxical responses to anabolic stimulation and identifying the mechanisms for this inconsistency in mobility-limited older adults may provide new targets for the treatment of sarcopenia. The objective of the current study was to assess circulating miRNA expression profiles in diametric response of leg lean mass in mobility-limited older individuals after a 6 month progressive resistance exercise training intervention (PRET). Participants were dichotomized by gain (Gainers; n = 33) or loss (Losers; n = 40) of leg lean mass after PRET. Gainers signifcantly increased fat-free mass. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. We then used a novel integrative approach to determine if differences in circulating miR-19b-3p potentially translate to augmented anabolic response in human skeletal muscle cells in vitro. Results from this analysis identified that overexpression of miR-19b-3p targeted and downregulated PTEN to facilitate increases in muscle protein synthetic rate. Together these data identify miR-19b-3p as a potent regulator of muscle anabolism that may contribute to an inter-individual response to PRET in mobility-limited older adults.

Keywords:  Aging; Exercise; Sarcopenia; Skeletal Muscle; microRNA

DOI:  https://doi.org/10.1152/ajpcell.00190.2021
Front Immunol. 2021 ;12 744509

Plasma Exosome-Enriched Extracellular Vesicles From Lactating Mothers With Type 1 Diabetes Contain Aberrant Levels of miRNAs During the Postpartum Period.

Caroline Frørup, Aashiq H Mirza, Reza Yarani, Lotte B Nielsen, Elisabeth R Mathiesen, Peter Damm, Jens Svare, Christian Engelbrekt, Joachim Størling, Jesper Johannesen, Henrik B Mortensen, Flemming Pociot, Simranjeet Kaur.

  Type 1 diabetes is an immune-driven disease, where the insulin-producing beta cells from the pancreatic islets of Langerhans becomes target of immune-mediated destruction. Several studies have highlighted the implication of circulating and exosomal microRNAs (miRNAs) in type 1 diabetes, underlining its biomarker value and novel therapeutic potential. Recently, we discovered that exosome-enriched extracellular vesicles carry altered levels of both known and novel miRNAs in breast milk from lactating mothers with type 1 diabetes. In this study, we aimed to characterize exosomal miRNAs in the circulation of lactating mothers with and without type 1 diabetes, hypothesizing that differences in type 1 diabetes risk in offspring from these groups are reflected in the circulating miRNA profile. We performed small RNA sequencing on exosome-enriched extracellular vesicles extracted from plasma of 52 lactating mothers around 5 weeks postpartum (26 with type 1 diabetes and 26 age-matched controls), and found a total of 2,289 miRNAs in vesicles from type 1 diabetes and control libraries. Of these, 176 were differentially expressed in plasma from mothers with type 1 diabetes (167 upregulated; 9 downregulated, using a cut-off of abs(log2FC) >1 and FDR adjusted p-value <0.05). Extracellular vesicles were verified by nanoparticle tracking analysis, transmission electron microscopy and immunoblotting. Five candidate miRNAs were selected based on their involvement in diabetes and immune modulation/beta-cell functions: hsa-miR-127-3p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p and hsa-miR-30d-5p. Real-time qPCR validation confirmed that hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p, and hsa-miR-30d-5p were significantly upregulated in lactating mothers with type 1 diabetes as compared to lactating healthy mothers. To determine possible target genes and affected pathways of the 5 miRNA candidates, computational network-based analyses were carried out with TargetScan, mirTarBase, QIAGEN Ingenuity Pathway Analysis and PantherDB database. The candidates showed significant association with inflammatory response and cytokine and chemokine mediated signaling pathways. With this study, we detect aberrant levels of miRNAs within plasma extracellular vesicles from lactating mothers with type 1 diabetes during the postpartum period, including miRNAs with associations to disease pathogenesis and inflammatory responses.

Keywords:  exosomes; extracellular vesicles; miRNAs; plasma; small RNA-Seq; type 1 diabetes

DOI:  https://doi.org/10.3389/fimmu.2021.744509
Dis Markers. 2021 ;2021 2924935

Exploring the Extracellular Vesicle MicroRNA Expression Repertoire in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis Treated with TNF Inhibitors.

Joanna Wielińska, Rachel E Crossland, Piotr Łacina, Jerzy Świerkot, Bartosz Bugaj, Anne M Dickinson, Katarzyna Bogunia-Kubik.

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) belong to the most common inflammatory rheumatic diseases. MicroRNAs (miRNAs) are small 18-22 RNA molecules that function as posttranscriptional regulators. They are abundantly present within extracellular vesicles (EVs), small intercellular communication vesicles that can be found in bodily fluids and that have key functions in pathological and physiological pathways. Recently, EVs have gained much interest because of their diagnostic and therapeutic potential. Using NanoString profiling technology, the miRNA repertoire of serum EVs was determined and compared in RA and AS patients before and after anti-TNF therapy to assess its potential use as a diagnostic and prognostic biomarker. Furthermore, possible functional effects of those miRNAs that were characterized by the most significant expression changes were evaluated using in silico prediction algorithms. The analysis revealed a unique profile of differentially expressed miRNAs in RA and AS patient serum EVs. We identified 12 miRNAs whose expression profiles enabled differentiation between RA and AS patients before induction of anti-TNF treatment, as well as 4 and 14 miRNAs whose repertoires were significantly changed during the treatment in RA and AS patients, respectively. In conclusion, our findings suggest that extracellular vesicle miRNAs could be used as potential biomarkers associated with RA and AS response to biological treatment.

DOI: https://doi.org/10.1155/2021/2924935
Tissue Cell. 2021 Oct 12. pii: S0040-8166(21)00185-3. [Epub ahead of print]73 101669

MiR-192-5p suppresses M1 macrophage polarization via epiregulin (EREG) downregulation in gouty arthritis.

Lixin An, Fuzai Yin.

  Gouty arthritis (GA) is a chronic inflammatory disease characterized by the deposition of monosodium urate (MSU) crystals within joints. MiR-192-5p is shown to be low-expressed in GA patients. However, the potential mechanism involving miR-192-5p in GA remains unclear. In the current study, a significant reduction in miR-192-5p and an increase in epiregulin (EREG) were observed in serum of GA patients, suggesting that miR-192-5p and EREG were involved in the pathogenic process of GA. A mouse GA model was established via 0.5 mg/20 μL MSU crystal administration. To investigate the effect of miR-192-5p on GA, mice were injected with miR-192-5p agomir or NC agomir before modeling. We found that miR-192-5p overexpression induced by miR-192-5p agomir reduced EREG expression, attenuated ankle joint swelling and synovial inflammatory cell infiltration and improved bone erosion in MSU-induced GA mice. MiR-192-5p decreased CD16/32+ (M1 marker) macrophages, but increased CD206 (M2 marker) expression in synovium of GA models. In vitro, RAW264.7 macrophages were stimulated with miR-192-5p mimic or NC mimic under IFNγ plus LPS-stimulated M1 polarization condition. MiR-192-5p reduced the release of inflammatory cytokines TNF-α and IL-1β, decreased iNOS expression, and inhibited CD16/32 expression, indicating the blockade of M1 macrophage activation. Luciferase reporter system revealed the target interaction between miR-192-5p and EREG. Further rescue experiments demonstrated that EREG overexpression partly reversed the inhibitory role of miR-192-5p on M1 macrophage polarization manifested by elevated iNOS and CD16/32 levels. Collectively, miR-192-5p ameliorates inflammatory response in GA by inhibiting M1 macrophage activation via inhibiting EREG protein.

Keywords:  Epiregulin; Gouty arthritis; M1 macrophages; miR-192-5p

DOI:  https://doi.org/10.1016/j.tice.2021.101669
Int J Gen Med. 2021 ;14 6807-6813

Potential Roles of miRNA-1245a Regulatory Networks in Sarcopenia.

Li An, Yao Wang.

   Objective: Sarcopenia is a universal problem in elderly individuals. The molecular regulatory mechanisms in sarcopenia are not well understood. In the present study, we explored a possible molecular mechanism involved in the pathogenesis of sarcopenia.
Methods: Differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus (GEO) database. Signaling pathways related to these DEGs were identified by gene set enrichment analysis (GSEA). Pearson correlation was calculated for all the pairwise comparisons of gene expression values between coding genes and DEGs. Interactions between the proteins encoded by the DEGs were identified using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses were performed to predict the functions of the DEGs.
Results: Three differentially expressed miRNAs and 5 differentially expressed mRNAs were identified in association with DEGs. We found that miRNA-1245a expression in patients with sarcopenia was higher than that in healthy controls. The GSEA showed that many pathways, such as the JAK-STAT signaling pathway and pathways related to glioma, gap junctions, and regulation of the actin cytoskeleton, were enriched in the high-miRNA-1245a-expression group. A total of 127 miRNA-1245a-related mRNAs were identified. The GO and KEGG analyses revealed that miRNA-1245a had a strong effect on a number of fundamental biological processes, such as kinase activity, that are related to the development of sarcopenia.
Conclusion: Our analyses indicate that miRNA-1245a may be a potential key molecule in the diagnosis and treatment of sarcopenia, which provides a basis for the research of miRNA in sarcopenia.

Keywords:  gene expression profiling; miRNA-1245a; sarcopenia

DOI:  https://doi.org/10.2147/IJGM.S334501
Cell Death Dis. 2021 Oct 29. 12(11): 1024

DCAF1-targeting microRNA-3175 activates Nrf2 signaling and inhibits dexamethasone-induced oxidative injury in human osteoblasts.

Jing Chen, Jin-Qian Liang, Yun-Fang Zhen, Lei Chang, Zhen-Tao Zhou, Xiong-Jie Shen.

Activation of nuclear-factor-E2-related factor 2 (Nrf2) signaling can protect human osteoblasts from dexamethasone-induced oxidative injury. DDB1 and CUL4 associated factor 1 (DCAF1) is a novel ubiquitin E3 ligase for Nrf2 protein degradation. We identified a novel DCAF1-targeting miRNA, miR-3175. RNA pull-down, Argonaute 2 RNA-immunoprecipitation, and RNA fluorescent in situ hybridization results confirmed a direct binding between miR-3175 and DCAF1 mRNA in primary human osteoblasts. DCAF1 3'-untranslated region luciferase activity and its expression were significantly decreased after miR-3175 overexpression but were augmented with miR-3175 inhibition in human osteoblasts and hFOB1.19 osteoblastic cells. miR-3175 overexpression activated Nrf2 signaling, causing Nrf2 protein stabilization, antioxidant response (ARE) activity increase, and transcription activation of Nrf2-dependent genes in human osteoblasts and hFOB1.19 cells. Furthermore, dexamethasone-induced oxidative injury and apoptosis were largely attenuated by miR-3175 overexpression in human osteoblasts and hFOB1.19 cells. Importantly, shRNA-induced silencing or CRISPR/Cas9-mediated Nrf2 knockout abolished miR-3175 overexpression-induced osteoblast cytoprotection against dexamethasone. Conversely, DFAC1 knockout, by the CRISPR/Cas9 method, activated the Nrf2 cascade and inhibited dexamethasone-induced cytotoxicity in hFOB1.19 cells. Importantly, miR-3175 expression was decreased in necrotic femoral head tissues of dexamethasone-taking patients, where DCAF1 mRNA was upregulated. Together, silencing DCAF1 by miR-3175 activated Nrf2 signaling to inhibit dexamethasone-induced oxidative injury and apoptosis in human osteoblasts.

DOI: https://doi.org/10.1038/s41419-021-04300-8
Cell Transplant. 2021 Jan-Dec;30:30 9636897211052977

Exosomal miR-1275 Secreted by Prostate Cancer Cells Modulates Osteoblast Proliferation and Activity by Targeting the SIRT2/RUNX2 Cascade.

Zihao Zou, Ranran Dai, Nan Deng, Wei Su, Ping Liu.

  Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the second leading cause of cancer mortality among men worldwide. Modulation of osteoblast activity is involved in PCa metastasis, and miR-1275 is also reported to regulate PCa metastasis; however, the association between cancer-derived exosomal miR-1275 and osteoblast activity is unclear. Here, we isolated exosomes from PC3-derived conditioned medium by ultracentrifugation. We found that miR-1275 could be transferred from PCa cells to osteoblasts via exosomes. Exosomal miR-1275 significantly accelerated the proliferation of osteoblasts and the expression levels of osteoblast-specific genes, such as osteocalcin (OCN), type I collagen (COL-1), and osteopontin (OPN). Moreover, exosomal miR-1275 increased the expression of RUNX2, a master modulator of osteoblast activity, by down-regulation of SIRT2, which in turn influenced the growth and activity of osteoblasts. Our findings indicate that PCa-derived exosomal miR-1275 promotes the proliferation and activity of osteoblasts via modulation of SIRT2/Runx2 signaling.

Keywords:  SIRT2; exosomes; miR-1275; osteoblast proliferation; prostate cancer

DOI:  https://doi.org/10.1177/09636897211052977
Cell Transplant. 2021 Jan-Dec;30:30 9636897211052959

CircRFWD2 Promotes Osteogenic Differentiation of human Dental Pulp Stem Cells by Targeting miR-6817-5p Through BMP-Smad and p38 MAPK Pathway.

Xinqi Huang, Xuefeng Pan, Bo Zhang, Wei Huang, Xiao Cen, Jun Liu, Zhihe Zhao.

  Dental pulp stem cells (DPSCs) are one promising cell source of mesenchymal stem cells in bone tissue engineering. However, it remains unknown that the molecules and signaling pathways involved in osteogenesis of DPSCs. Hence, this study investigated the functional roles and underlying mechanisms of circRFWD2 during osteogenesis of DPSCs. Knockdown of circRFWD2 suppressed osteogenesis of DPSCs significantly. Mechanistically, circRFWD2 could crosstalk with miR-6817-5p, which was an inhibitor of DPSCs osteogenesis. MiR-6817-5p functioned as a sponge of BMPR2, which regulated the phosphorylation of Smad5 and p38 to impact osteogenesis activity of DPSCs. Collectively, circRFWD2/miR-6817-5p/BMPR2 axis could regulate DPSCs osteogenesis via BMP-Smad and p38 MAPK pathway, which are novel mechanisms in the osteogenic differentiation of DPSCs and suggest potential therapeutic methods for bone defects regeneration.

Keywords:  BMP-Smad pathway; BMPR2; bone tissue engineering; circRFWD2; miR-6817-5p; p38 MAPK pathway

DOI:  https://doi.org/10.1177/09636897211052959
J Clin Lab Anal. 2021 Oct 28. e24076

Long non-coding RNA NEAT1 and its targets (microRNA-21 and microRNA-125a) in rheumatoid arthritis: Altered expression and potential to monitor disease activity and treatment outcome.

Junfeng Yang, Shanfu Wang, Lei Liu, Jianwei Wang, Yang Shao.

   BACKGROUND: The present study aimed to explore the association of long non-coding RNA nuclear-enriched abundant transcript 1 (lnc-NEAT1) with inflammation, disease activity, treatment outcome, and its targets (microRNA [miR]-21 and miR-125a) in patients with rheumatoid arthritis (RA).
METHODS: Peripheral blood mononuclear cells were sampled from 130 RA patients at baseline, week (W) 6, and W12, as well as from 60 healthy controls (HCs) after enrollment. Meanwhile, the expressions of lnc-NEAT1, miR-21, and miR-125a were detected by reverse transcription-quantitative polymerase chain reaction.
RESULTS: lnc-NEAT1 was elevated, but miR-21 and miR-125a were declined in RA patients compared with HCs (all p < 0.001); meanwhile, lnc-NEAT1 was negatively correlated with miR-21 and miR-125a (both p < 0.05) in RA patients. Besides, elevated lnc-NEAT1 but declined miR-21 and miR-125a were correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein and the 28-joint Disease Activity-ESR score (all p < 0.05) in RA patients. Moreover, lnc-NEAT1 was declined from baseline to W12 in RA patients (p < 0.001). Additionally, lnc-NEAT1 at W12 was declined in response patients compared with non-response patients (p = 0.006), and also decreased in remission patients compared with non-remission patients (p < 0.001).
CONCLUSION: lnc-NEAT1 and its targets (miR-21 and miR-125a) correlate with RA risk and disease activity, and declined lnc-NEAT1 associates with better treatment outcome to some extent in RA patients, suggesting that lnc-NEAT1 might be a potential biomarker to monitor disease activity and treatment outcome in RA.

Keywords:  disease activity; lncRNA NEAT1; miR-21 and miR-125a; rheumatoid arthritis; treatment outcome

DOI:  https://doi.org/10.1002/jcla.24076