The Supercarbonate Apatite-MicroRNA Complex Inhibits Dextran Sodium Sulfate-Induced Colitis

Abstract

The incidence of inflammatory bowel disease (IBD) is increasing. Nucleic acid-based medicine has potential as a next-generation treatment, but it is rarely successful with IBD. The aim of this study was to establish a microRNA-based therapy in an IBD model. For this purpose, we used microRNA-29 (miR-29) and a supercarbonate apatite (sCA) nanoparticle as a drug delivery system. Injection of sCA-miR-29a-3p or sCA-miR-29b-3p into mouse tail veins markedly prevented and restored inflammation because of dextran sulfate sodium (DSS)-induced colitis. RNA sequencing analysis revealed that miR-29a and miR-29b could inhibit the interferon-associated inflammatory cascade. Subcutaneous injection of sCA-miR-29b also potently inhibited inflammation, and it efficiently targeted CD11c+ dendritic cells (DCs) among various types of immune cells in the inflamed mucosa. RT-PCR analysis indicated that the miR-29 RNAs in CD11c+ DCs suppressed the production of interleukin-6 (IL-6), transforming growth factor β (TGF-β), and IL-23 subunits in DSS-treated mice. This may inhibit Th17 differentiation and subsequent activation, which is critical in IBD pathogenesis. In vivo experiments using a non-natural artificial microRNA sequence revealed that targeting of DCs in the inflamed colon is an exceptional feature of sCA. This study suggests that sCA-miR-29s may open a new avenue in nucleic acid-based medicine for IBD treatment.

Concentrates of two subsets of extracellular vesicles from cow’s milk modulate symptoms and inflammation in experimental colitis

“…MiR-29b diminishes dendritic cells’ apoptosis and cytokine production 62 . However, its deletion exacerbates UC, while its overexpression helps managing the disease 63 . Whereas miR-29b is known to prevent inflammation 64 , it increases collagen production and fibrosis in IBD 65 .…”

MicroRNA-29a Counteracts Glucocorticoid Induction of Bone Loss through Repressing TNFSF13b Modulation of Osteoclastogenesis

“…Moreover, the miR-29 family regulates myogenesis of muscle stem cells [16], chondrogenic differentiation of mesenchymal stem cells [17] and fibrosis matrix formation in inflamed tissue [18]. miR-29 signaling also modulates immune cell activation in multiple sclerosis [19], the host immune response [20] and inflammatory reaction in colitis [21]. We previously revealed that glucocorticoid induced bone loss and marrow adipose overdevelopment along with decreased miR-29a expression [22].…”

miR-4711-5p regulates cancer stemness and cell cycle progression via KLF5, MDM2 and TFDP1 in colon cancer cells

“… 21 In earlier studies, we had shown that sCA nanoparticles successfully delivered various nucleic acids or low molecular weight reagents in tumour or IBD (inflammatory bowel disease) model mice with no resulting apparent abnormalities in the body weight, blood chemistry tests or histology of normal organs of the mice. 18 – 22 , 53 – 56 Moreover, recent review articles have described various miRNA-based therapeutics, most of which employ local injection into tumours, and introduced sCA as a hopeful systemic strategy that could be delivered via intravenous administration. 50 , 57 Aiming towards clinical application, we have successfully developed an even less toxic and more efficient delivery system platform that is considered promising in terms of clinical potential.…”

“…We conducted RNA sequencing as previously described. 18 The library was prepared using a TruSeq Stranded mRNA Sample Prep Kit (Illumina, San Diego, CA, USA). Sequencing was performed using the Illumina HiSeq 2500 platform in 75-base single-end mode.…”