Obesity regulates miR‐467/HoxA10 axis on osteogenic differentiation and fracture healing by BMSC‐derived exosome LncRNA H19

Abstract

This study explored the therapeutic effect of bone marrow mesenchymal stem cell‐derived exosomes on the treatment of obesity‐induced fracture healing. Quantitative real‐time PCR was used to detect the expression of lncRNA H19, miR‐467 and Hoxa10 and combined with WB detection to detect osteogenic markers (RUNX2, OPN, OCN). Determine whether exosomes have entered BMSCs by immunofluorescence staining. Alkaline phosphatase (ALP) and alizarin red staining (ARS) staining were used to detect ALP activity and calcium deposition. We found that high‐fat treatment can inhibit the secretion of BMSCs‐derived exosomes and affect the expression of H19 carried by them. In vivo and in vitro experiments show that high‐fat or obesity factors can inhibit the expression of osteogenic markers and reduce the staining activity of ALP and ARS. The treatment of exosomes from normal sources can reverse the phenomenon of osteogenic differentiation and abnormal fracture healing. Further bioinformatics analysis found that miR‐467 as a regulatory molecule of lncRNA H19 and Hoxa10, and we verified the targeting relationship of the three through dual luciferase report experiments. Further, we found similar phenomena in ALP and ARS staining. Bone marrow mesenchymal stem cell‐derived exosomes improve fracture healing caused by obesity.

Review of the Role of Mesenchymal Stem Cells and Exosomes Derived from Mesenchymal Stem Cells in the Treatment of Orthopedic Disease

“…In the process of bone formation, fat is usually considered as a negative regulatory factor. One study showed that the BMSC-Exo lncRNA-H19 in an obesity model absorbed miRNA-188 through ceRNA inhibited the osteogenesis of mouse BMSC and turned to adipogenic differentiation; the authors also found that BMSC-exo lncRNA-H19 could competitively bind to miRNA-467 and inhibit the expression of Hoxa10, thus inhibiting osteogenesis [ 38 ]. The effect of obesity on the expression profile of miRNA in ADSC-Exos may have a direct impact on the function of exosomes.…”

Application of exosome-derived noncoding RNAs in bone regeneration: Opportunities and challenges

“…Previous studies have confirmed that Hoxa10 can participate in regulating osteogenic differentiation[ 104 ]. More recently, Wang et al [ 105 ] demonstrated that exo-H19 can regulate the expression of Hoxa10 through competitive binding to miR-467 and promote osteogenic differentiation[ 105 ]. Moreover, exo-lncRNA-H19 stimulates osteogenesis via mediating Angpt1/Tie2-NO signaling in mice[ 106 ].…”

Noncoding RNA in Extracellular Vesicles Regulate Differentiation of Mesenchymal Stem Cells

“…Exosomal miR-92a-3p regulates C/EBPα at the posttranscriptional level to block adipogenic differentiation of adipose stem cells (121). Obesity and high-fat treatment break the bone-fat equilibrium and downregulate the expression of lnc H19 in the circulation and output of BMSC-origin exosomes (122).…”