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MiR-26a Rescues Bone Regeneration Deficiency of Mesenchymal Stem Cells Derived From Osteoporotic Mice.

ABSTRACT: Osteoporosis, caused by a relative increase of bone resorption over bone formation, is characterized by decreased bone mass and bone strength, resulting in an increased incidence of bone fractures, which often leads to further disability and early mortality in the elderly due to impaired bone healing ability. The majority of therapeutics currently used in clinics for the treatment of osteoporosis are antiresorptive agents that exert their clinical effect by decreasing the rate of bone resorption. However, strategies solely aimed at antiresorption have limited therapeutic efficacy in restoring bone remodeling balance and enhancing osteoporotic fracture healing. Here, we report that miR-26a plays a critical role in modulating bone formation during osteoporosis. We found that miR-26a treatment could effectively improve the osteogenic differentiation capability of mesenchymal stem cells isolated from littermate-derived ovariectomized osteoporotic mice both in vitro and in vivo. MiR-26a exerts its effect by directly targeting Tob1, the negative regulator of BMP/Smad signaling pathway by binding to the 3'-untranslated region and thus repressing Tob1 protein expression. Our findings indicate that miR-26a may be a promising therapeutic candidate to enhance bone formation in treatment of osteoporosis and to promote bone regeneration in osteoporotic fracture healing.

SUBMITTER: Li Y

PROVIDER: S-EPMC4817873 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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MiR-26a Rescues Bone Regeneration Deficiency of Mesenchymal Stem Cells Derived From Osteoporotic Mice.

Li Yan Y Fan Longkun L Hu Jiang J Zhang Leilei L Liao Li L Liu Shiyu S Wu Dan D Yang Ping P Shen Lijuan L Chen Jihua J Jin Yan Y

Molecular therapy : the journal of the American Society of Gene Therapy 20150608 8

Osteoporosis, caused by a relative increase of bone resorption over bone formation, is characterized by decreased bone mass and bone strength, resulting in an increased incidence of bone fractures, which often leads to further disability and early mortality in the elderly due to impaired bone healing ability. The majority of therapeutics currently used in clinics for the treatment of osteoporosis are antiresorptive agents that exert their clinical effect by decreasing the rate of bone resorption ...[more]

PMID: 26050992

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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.

Project description:BackgroundOsteoporosis is characterized by low systemic bone mineral content and destruction of bone microarchitecture. Promoting bone regeneration and reversing its loss by infusion of exogenous bone marrow mesenchymal stem cells (BMSCs) is a potentially effective treatment for osteoporosis. However, their limited migration to target organs reduces the therapeutic effect of the cells. Stromal cell-derived factor 1 (SDF1) is a chemokine that induces targeted cell migration through the SDF1/CXCR4 (C-X-C chemokine receptor 4) axis and can induce migration of exogenous mesenchymal stem cells to sites of high SDF1 concentration. There are no studies on BMSCs overexpressing SDF1 (SDF1-BMSCs) in osteoporotic mice in vivo. We aimed to investigate if the increased SDF1 concentration facilitated cell migration to the bone.MethodsWe used lentivirus to construct BMSCs overexpressing SDF1 or knocking down CXCR4. We verified the proliferation ability of the cells in vitro using Cell Counting Kit-8 (CCK8) and 5-Bromodeoxyuridinc (BrdU), the migration ability of the cells using Transwell, and the osteogenic and lipogenic ability of the cells using osteogenic and lipogenic induction solutions. In in vivo experiments, we induced osteoporosis in 72 female mice by ovariectomy and injected different groups of cells via the tail vein. Femoral tissue samples were collected for a fixed time, and the osteogenic and homing abilities of the cells were verified by MicroCT and tissue section staining.ResultsWe successfully demonstrated that high expression of SDF1 promoted cell proliferation and migration in vitro, without affecting their cell differentiation ability. In an ovariectomized mouse model, SDF1-BMSCs were more likely to be home to the femur than the BMSCs, had a better pro-osteogenic ability, and had higher expression of Wnt-1. Blocking the SDF1/CXCR4 axis reduced the homing of exogenous mesenchymal stem cells (MSCs) to the femur and their osteogenic capacity.ConclusionsSDF1-BMSCs can further promote bone formation by increasing the number of cells homing to the femur in osteoporotic mice. Our study shows that stem cells can promote their proliferation and home to the femur via the SDF1/CXCR4 axis and further help bone formation via Wnt-1 signaling.

Dataset Information

MiR-26a Rescues Bone Regeneration Deficiency of Mesenchymal Stem Cells Derived From Osteoporotic Mice.

Publications

MiR-26a Rescues Bone Regeneration Deficiency of Mesenchymal Stem Cells Derived From Osteoporotic Mice.

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