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. 2023 Oct;39(5):2243-2257.
doi: 10.1007/s10565-022-09713-5. Epub 2022 May 13.

Urine-derived stem cells-extracellular vesicles ameliorate diabetic osteoporosis through HDAC4/HIF-1α/VEGFA axis by delivering microRNA-26a-5p

Dan Zhang  1 , Jian Du  1 , Min Yu  2 , Linna Suo  3
Affiliations

Urine-derived stem cells-extracellular vesicles ameliorate diabetic osteoporosis through HDAC4/HIF-1α/VEGFA axis by delivering microRNA-26a-5p

Dan Zhang et al. Cell Biol Toxicol. 2023 Oct.

Abstract

Critical roles of stem cell-extracellular vesicles (EVs) in the management of osteoporosis have been documented. Here, this study was designed to enlarge the research of the specific effects and underlying mechanism of urine-derived stem cells-EVs (USCs-EVs) on osteoporosis in diabetes rats. Firstly, miR-26a-5p and histone deacetylase 4 (HDAC4) expression in USCs of rats after diabetic osteoporosis (DOP) modeling induced by streptozotocin injection was determined, followed by study of their interaction. Then, USCs-EVs were co-cultured with osteogenic precursor cells, the effects of miRNA-26a-5p (miR-26a-5p) on osteoblasts, osteoclasts, bone mineralization deposition rate were evaluated. Meanwhile, the effect of USCs-EVs carrying miR-26a-5p on DOP rats was assessed. Elevated miR-26a-5p was seen in USCs-EVs which limited HDAC4 expression. Moreover, USCs-EVs delivered miR-26a-5p to osteogenic precursor cells, thereby promoting their differentiation, enhancing the activity of osteoblasts, and inhibiting the activity of osteoclasts, thereby preventing DOP through the activation of hypoxia inducible factor 1 subunit alpha (HIF-1α)/vascular endothelial growth factor A (VEGFA) pathway by repressing HDAC4. In a word, USCs-EVs-miR-26a-5p is a promising therapy for DOP by activating HIF-1α/VEGFA pathway through HDAC4 inhibition. 1. USCs-EVs-miR-26a-5p targeted HDAC4 and limited HDAC4 expression. 2. miR-26a-5p was delivered by USCs-EVs into osteoblast precursor cells. 3. USCs-EVs-miR-26a-5p promoted the differentiation of osteoblast precursor cells into osteoblasts. 4. miR-26a-5p delivered by USCs-EVs could inhibit HDAC4. 5. USCs-EVs-miR-26a-5p could prevent the pathogenesis of DOP via HIF-1α/VEGFA aix.

Keywords: Diabetes; Extracellular vesicles; HDAC4; HIF-1α; Histone deacetylase; Osteoporosis; Urine-derived stem cells; VEGFA; microRNA-26a-5p.

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