Abstract
MicroRNAs (miRs) regulate inflammation and BMP antagonists, thus they have potential uses as therapeutic reagents. However, the molecular function of miR-200c in modulating proinflammatory and bone metabolic mediators and osteogenic differentiation is not known. After miR-200c was transduced into a human embryonic palatal mesenchyme (HEPM) (a cell line of preosteoblasts), using lentiviral vectors, the resulting miR-200c overexpression increased osteogenic differentiation biomarkers, including osteocalcin (OCN) transcripts and calcium content. miR-200c expression also down-regulated interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand (CCL)-5 under lipopolysaccharide (LPS) stimulation and increased osteoprotegerin (OPG) in these cells. miR-200c directly regulates the expression of IL-6, IL-8 and CCL-5 transcripts by binding to their 3’UTRs. A plasmid-based miR-200c inhibitor effectively reduces their binding activities. Additionally, miR-200c delivered using polyethylenimine (PEI) nanoparticles effectively inhibits IL-6, IL-8 and CCL-5 in primary human periodontal ligament fibroblasts and increases the biomarkers of osteogenic differentiation in human bone marrow mesenchymal stem cells (MSCs), including calcium content, ALP, and Runx2. These data demonstrate that miR-200c represses IL-6, IL-8 and CCL-5 and improves osteogenic differentiation. miR-200c may potentially be used as an effective means to prevent periodontitis-associated bone loss by arresting inflammation and osteoclastogenesis and enhancing bone regeneration.
Highlights
It has been reported that approximately half of American adults aged 30 years and older have periodontitis, and the prevalence of periodontitis further increase in aged populations and in patients with diabetes or who smoke [1, 2]
We found that overexpression of miR-200c in the human preosteoblast cell line effectively suppresses multiple proinflammatory mediators, including IL-6, IL-8, and CCL-5, and increases OPG and osteocalcin (OCN) and calcium content
The level of miR-200c expression measured using real-time PCR was approximately 2x104-fold higher in human embryonic palatal mesenchyme (HEPM) cells infected with miR-200c than in non-treated control cells and the cells transfected with scrambled miRs, while there was limited miR-200c expression in non-treated HEPM cells and the cells with scrambled miRs (Fig 1B)
Summary
It has been reported that approximately half of American adults aged 30 years and older have periodontitis, and the prevalence of periodontitis further increase in aged populations and in patients with diabetes or who smoke [1, 2]. TLR-mediated signaling pathways lead to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key proinflammatory transcription factor [11]. These cytokines and transcription factors in turn further amplify the inflammatory response and lead to production of lytic enzymes and stimulate the production of chemokines, including IL-6, IL-8 and CCL-5 [8,9,10, 12]. Reducing the expression and activation of proinflammatory and bone metabolic mediators that activate osteoclastogenesis and bone resorption may serve as an effective strategy to prevent and arrest the development of periodontal bone loss. Inhibiting proinflammatory mediators may prevent and restore periodontitis-associated bone loss
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