Abstract
The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is essential for bone formation, and its imbalance can lead to bone diseases such as osteoporosis. It is reported that PIWI-interacting RNA-36741 (piR-36741) is up-regulated during the osteogenic differentiation, but its role in regulating osteogenic differentiation remains unclear. Here, the primary human BMSCs were used to induce osteogenic differentiation, and the expression of piR-36741 and METTL3 (methyltransferase like 3) was up-regulated during the osteogenic differentiation of BMSCs. Moreover, interference with piR-36741 or METTL3 markedly hindered the osteogenic differentiation of BMSCs, which was manifested by a reduction in osteoblast marker expression (including RUNX2, COL1A1, OPN and OCN), osteogenic phenotype and matrix mineralization. Mechanistically, the piR-36741-PIWIL4 complex directly interacted with METTL3 and prevented METTL3-mediated m6A modification of BMP2 mRNA transcripts, thereby promoting BMP2 expression. And overexpression of BMP2 reversed the inhibitory effect of piR-36741 silence on osteogenic differentiation and the Smad pathway activity. In addition, administration with piR-36741 mimic alleviated ovariectomy-induced osteoporosis in mice. In conclusion, piRNA-36741 overexpression promoted osteogenic differentiation of BMSCs and mitigated ovariectomy-induced osteoporosis through METTL3-mediated m6A methylation of BMP2 transcripts.
Highlights
Osteoporosis (OP) is a systemic bone disease characterized by bone loss
We revealed the potential molecular mechanism of piR-36741 in regulating osteogenic differentiation, which involved methyltransferase like 3 (METTL3)-mediated m6A methylation regulation of BMP2 mRNA
PiR-36741 and METTL3 expression was upregulated in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs)
Summary
Osteoporosis (OP) is a systemic bone disease characterized by bone loss. It is manifested as a decrease in bone mass and structural degradation of bone tissue, resulting in impaired bone strength and increased possibility of fragility fractures [1]. The basic pathogenesis of OP is the imbalance between osteoblast bone formation and osteoclast bone resorption [2]. Bone marrow mesenchymal stem cells (BMSCs) are the precursor cells of osteoblasts, which have the ability to differentiate into multiple cell lineages (osteoblasts, chondrocytes, bone marrow stromal cells and adipocytes) and self-renewal [3].
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