Quercetin promotes bone marrow mesenchymal stem cell proliferation and osteogenic differentiation through the H19/miR-625-5p axis to activate the Wnt/β-catenin pathway

Abstract

Background Quercetin and H19 can promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). However, whether quercetin regulates H19 expression to promote osteogenic differentiation of BMSCs is unclear. Methods BMSC proliferation, matrix mineralization, and alkaline phosphatase (ALP) activity were assessed using the Cell Counting Kit-8, ALP assay kit, and alizarin red staining kit, respectively. Expression of H19, miR-625-5p, BMP-2, osteocalcin, and RUNX2 were measured by qRT-PCR; β-catenin protein level was measured by western blotting. Results Quercetin promoted BMSC proliferation, enhanced ALP activity, and upregulated the expression of BMP-2, osteocalcin, and RUNX2 mRNAs, suggesting that it promoted osteogenic differentiation of BMSCs. Moreover, quercetin increased H19 expression, while the effect of quercetin on BMSCs was reversed by silencing H19 expression. Additionally, miR-625-5p, interacted with H19, was downregulated during quercetin-induced BMSC osteogenic differentiation, which negatively correlated with H19 expression. Silencing miR-625-5p expression promoted BMSC proliferation and osteogenic differentiation, whereas miR-625-5p overexpression weakened the effect of quercetin on BMSCs. Finally, quercetin treatment or downregulation of miR-625-5p expression increased β-catenin protein level in BMSCs. Upregulation or downregulation of miR-625-5p or H19 expression, respectively, inhibited β-catenin protein level in quercetin treated-BMSCs. Conclusion H19 promotes, while miR-625-5p inhibits BMSC osteogenic differentiation. Quercetin activates the Wnt/β-catenin pathway and promotes BMSC osteogenic differentiation via the H19/miR-625-5p axis.

The Role of Flavonoids in the Osteogenic Differentiation of Mesenchymal Stem Cells

“…Quercetin also promoted the differentiation and proliferation of BMSCs through inhibiting NF-κB activation and β-catenin degradation stimulated by TNF-α ( Yuan et al, 2018 ). Bian et al also observed Wnt/β-catenin pathway activation played an important role in the osteogenic differentiation of quercetin treated-BMSCs ( Bian et al, 2021 ). Quercetin stimulated osteogenic differentiation of BMSCs by increasing connexin 43 expressions ( Zhang et al, 2020 ) which could enhance osteogenic differentiation of BMSCs by promoting GSK-3β/β-catenin signaling pathways ( Lin FX.…”

Role of mechano-sensitive non-coding RNAs in bone remodeling of orthodontic tooth movement: recent advances

“…XIST miR-214-3p Unknown Inhibit osteogenic differentiation of PDLSCs [109] miR-29b-3p RUNX2 Inhibit OB differentiation [110] miR-135 RANKL Inhibit OB differentiation [111] miR-375-3p AKT/mTOR Inhibit OB differentiation [112] DANCR Unknown WNT Promote osteogenic differentiation of PDLSC [113] Unknown EZH2↓, Runx2↑ Increase OB proliferation and decrease OB apoptosis [114] miR-758 Notch2 Suppress osteogenic differentiation of PDLSC [115] Jagged1 Notch Facilitate osteoclast formation and root resorption [116] TUG1 miR-222-3p Smad2/7 Facilitate osteogenic differentiation of PDLSC [117] Unknown Wnt/β-catenin Promote OB proliferation and differentiation [118] miR-545-3p CNR2 Promote OB proliferation and differentiation [119] miR-34a FGFR1 Promote OB proliferation and inhibit apoptosis [61] Unknown MafB Stimulate osteoclast formation [120] PCAT1 miR-106a-5p BMP2 Promote osteogenic differentiation of PDLSC [121] H19 miR-675 TGF-β1/Smad3/HDAC Promote osteogenic differentiation of hMSC [122] miR-22, -141 Wnt/β-catenin Potentiate osteogenesis [123] miR-138 FAK Unknown [124] miR-188 LCoR Promote osteogenic differentiation of mBMSC [125] miR-19b-3p Unknown Promote cell proliferation and osteogenic differentiation of BMSCs [126] miR-675 APC Promote osteogenic differentiation of BMSC [127] miR-149 SDF-1 Stimulates osteogenic differentiation of BMSC [128] miR-185-5p IGF1 Promote matrix mineralization [129] miR-140-5p SATB2 Promote osteogenic differentiation of BMSC [130] miR-467 HoxA10 Promote osteogenic differentiation of BMSC [131] miR-106 Angpt1 Promote osteogenesis and angiogenesis [132] miR-625-5p Wnt/β-catenin Promote BMSC proliferation and osteogenic differentiation [133] miR-541-3p Wnt/β-catenin Promote osteogenic differentiation of BMSC [134] miR-532-3p SIRT1 Promote osteogenic differentiation of BMSC [135] miR Wu [117] revealed that TUG1 accelerates the osteogenic differentiation by sponging m...…”

“…A cluster of papers had revealed that H19 was involved in miR-19b-3p [126], miR-675/APC axis [127], micR-149/SDF-1 axis [128], miR-185-5p/IGF1 axis [129], miRNA-140-5p/SATB2 axis [130], miR-467/HoxA10 [131], miR-106/Angpt1 axis [132], miR-625-5p/Wnt/βcatenin axis [133], miR-541-3p/Wnt/β-catenin axis [134], miR-532-3p/SIRT1 axis [135], and miR-214-5p/BMP2 axis [136]. Additionally, the effects of the H19 on osteogenic differentiation were summarized in Zhou's [154] and Wang's [155] review.…”

The Emerging Role of Non-Coding RNAs in Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells

“…MiRNAs mediate the osteogenic differentiation processes of drugs, factors, etc. Overexpression of miR-625-5p reverses the promoting effect of quercetin on osteogenic differentiation of BMSCs ( Bian et al, 2021 ). Wang et al (2016) showed that miR-150-3p targets β-catenin and inhibits tumor necrosis factor-α (TNF-α) induced osteogenic differentiation of BMSCs, which inhibits the inflammation response during bone formation.…”

“…Quercetin has been proved to affect osteogenesis and osteoclastgenesis by regulation of a number of mechanisms, including mediating the expression of osteoprotegerin, and MAPK signaling ( Wong et al, 2020 ). Quercetin also plays a significant role in accelerating osteogenesis via interaction with H19 by sponging miR-625-5p, and ultimately activates Wnt/β-catenin pathway ( Bian et al, 2021 ) ( Figure 4 and Table 3 ). Bi et al (2020) found that H19 expression is increased in a time-dependent manner during osteogenesis.…”