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CircFOXP1/FOXP1 promotes osteogenic differentiation in adipose-derived mesenchymal stem cells and bone regeneration in osteoporosis via miR-33a-5p.

ABSTRACT: Osteoporosis (OP) is defined by bone mass loss and structural bone deterioration. Currently, there are no effective therapies for OP treatment. Circular RNAs (circRNAs) have been reported to have an important function in stem cell osteogenesis and to be associated with OP. Most circRNA roles in OP remain unclear. In the present study, we employed circRNA microarray to investigate circRNA expression patterns in OP and non-OP patient bone tissues. The circRNA-miRNA-mRNA interaction was predicted using bioinformatic analysis and confirmed by RNA FISH, RIP and dual-luciferase reporter assays. ARS and ALP staining was used to detect the degree of osteogenic differentiation in human adipose-derived mesenchymal stem cells (hASCs) in vitro. In vivo osteogenesis in hASCs encapsulated in collagen-based hydrogels was tested with heterotopic bone formation assay in nude mice. Our research found that circFOXP1 was significantly down-regulated in OP patient bone tissues and functioned like a miRNA sponge targeting miR-33a-5p to increase FOXP1 expression. In vivo and in vitro analyses showed that circFOXP1 enhances hASC osteogenesis by sponging miR-33a-5p. Conversely, miR-33a-5p inhibits osteogenesis by targeting FOXP1 3'-UTR and down-regulating FOXP1 expression. These results determined that circFOXP1 binding to miR-33a-5p promotes hASC osteogenic differentiation by targeting FOXP1. Therefore, circFOXP7ay prevent OP and can be used as a candidate OP therapeutic target.

SUBMITTER: Shen W

PROVIDER: S-EPMC7687013 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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CircFOXP1/FOXP1 promotes osteogenic differentiation in adipose-derived mesenchymal stem cells and bone regeneration in osteoporosis via miR-33a-5p.

Shen Wanxiang W Sun Bin B Zhou Chenghong C Ming Wenyi W Zhang Shaohua S Wu Xudong X

Journal of cellular and molecular medicine 20200930 21

Osteoporosis (OP) is defined by bone mass loss and structural bone deterioration. Currently, there are no effective therapies for OP treatment. Circular RNAs (circRNAs) have been reported to have an important function in stem cell osteogenesis and to be associated with OP. Most circRNA roles in OP remain unclear. In the present study, we employed circRNA microarray to investigate circRNA expression patterns in OP and non-OP patient bone tissues. The circRNA-miRNA-mRNA interaction was predicted u ...[more]

PMID: 32996692

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Project description:BackgroundAs one of the most common chronic diseases in the world, osteoporosis occurs especially in postmenopausal women. Circular RNAs (circRNAs) are emerging as major drivers in human disease. The aim of the present study was to analyse circRNA expression profiles in osteoporosis and to explore the clinical significance and the regulatory molecular mechanism of hsa_circ_0006859 during osteoporosis.MethodsExosomes were isolated from clinically collected serum samples. A circRNA microarray was performed to screen differentially expressed circRNAs. Quantitative real-time PCR (qRT-PCR) and western blot were performed to analyse target gene mRNA expression and protein expression. Alizarin red staining (ARS) was performed to evaluate the mineralization ability of human bone marrow mesenchymal stem cells (hBMSCs). Oil Red O staining was performed to evaluate the lipid droplet formation ability of hBMSCs. Bioinformatics analysis and the luciferase reporter assay were performed to investigate the interaction between two genes.ResultsHsa_circ_0006859 was identified as one of the most upregulated circRNAs in the microarray analysis. Hsa_circ_0006859 in exosomes was upregulated in osteoporosis patients compared to healthy controls. Hsa_circ_0006859 differentiated osteopenia or osteoporosis patients from healthy controls with high sensitivity and specificity. Hsa_circ_0006859 suppressed osteoblastic differentiation and promoted adipogenic differentiation of hBMSCs. Hsa_circ_0006859 directly bound to miR-431-5p, and ROCK1 was identified as a novel target gene of miR-431-5p. Hsa_circ_0006859 is a competing endogenous RNA (ceRNA) of miR-431-5p that promotes ROCK1 expression. Hsa_circ_0006859 suppressed osteogenesis and promoted adipogenesis by sponging miR-431-5p to upregulate ROCK1.ConclusionsExosomal hsa_circ_0006859 is a potential biomarker for postmenopausal osteoporosis and controls the balance between osteogenesis and adipogenesis in hBMSCs by sponging miR-431-5p.

Project description:BackgroundSufficient vascular network plays an important role in the repair of bone defects. Bone morphogenetic protein 2 (BMP2) being a key regulator of angiogenesis has attracted the attention of researchers. In addition, evidence has suggested that BMP2 coordinates with microRNAs (miRNAs) to form intracellular networks regulating mesenchymal stem cells (MSCs) angiogenesis. Elucidating the underlying mechanisms that are regulating adipose-derived mesenchymal stem cells (ADSCs) angiogenesis might provide more effective method to enhance bone regeneration.MethodsWe identified the specific miRNA in rat ADSCs during BMP2-induced angiogenesis and chose the most significant differentially expressed miRNA, miR-672. Three lentiviral system named Lenti-miR-672, Lenti-as-miR-672, and Lenti-miR-NC were transduced into the ADSCs individually. Then, the quantitative real-time polymerase chain reaction (qPCR), western blotting, and blood vessel formation analysis were performed to investigate the effects of miR-672 on ADSCs angiogenesis. Bioinformation platforms were used to screen the potential target of miR-672. Small interfering RNA (siRNA) against TIMP2 (si-TIMP2) mRNA were obtained from GenePharma, and then si-TIMP2 miRNA and miR-672 were co-transfected into ADSCs to detect the effects of TIMP2 on angiogenesis. Calcium phosphate cement (CPC) scaffolds that seeded the lentiviral-modified ADSCs were constructed to test the vascularized bone regeneration in vivo.ResultsOur data showed that after the angiogenesis of ADSCs induced by BMP2, miR-672 was the most significantly upregulated miRNA. Overexpression of miR-672 promoted the angiogenesis of ADSCs, while knockdown of miR-672 repressed the angiogenesis of ADSCs. The bioinformation prediction showed that TIMP2 might be the one of miR-672' potential targets. TIMP2 protein expression was gradually decreased in ADSCs with overexpressed miR-672. And the angiogenic factors were upregulated in the ADSCs which were transduced with si-TIMP2. Then, the CPC scaffolds coupled the miR-672-modified ADSCs and showed the good potential in vascularized bone regeneration. The overexpressed miR-672 could greatly enhance the blood vessel volume and Microfil-labeled blood vessel numbers in newly formed bone.ConclusionBMP2 could promote the angiogenesis of ADSCs through stimulating the expression of miR-672 in ADSCs. miR-672 acted as a positive regulator on the angiogenesis of ADSCs, and incorporating the miR-672-modified ADSCs in the CPC could significantly promote the vascularization and the bone regeneration.

Dataset Information

CircFOXP1/FOXP1 promotes osteogenic differentiation in adipose-derived mesenchymal stem cells and bone regeneration in osteoporosis via miR-33a-5p.

Publications

CircFOXP1/FOXP1 promotes osteogenic differentiation in adipose-derived mesenchymal stem cells and bone regeneration in osteoporosis via miR-33a-5p.

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