miR-206 inhibits osteogenic differentiation of bone marrow mesenchymal stem cells by targetting glutaminase

Abstract

Osteoblast-mediated bone formation is a complex process involving various pathways and regulatory factors, including cytokines, growth factors, and hormones. Investigating the regulatory mechanisms behind osteoblast differentiation is important for bone regeneration therapy. miRNAs are known as important regulators, not only in a variety of cellular processes, but also in the pathogenesis of bone diseases. In the present study, we investigated the potential roles of miR-206 during osteoblast differentiation. We report that miR-206 expression was significantly down-regulated in human bone marrow mesenchymal stem cells (BMSCs) at days 7 and 14 during osteogenic induction. Furthermore, miR-206 overexpressing BMSCs showed attenuated alkaline phosphatase (ALP) activity, Alizarin Red staining, and osteocalcin secretion. The mRNA levels of osteogenic markers, Runx2 and Osteopontin (OPN), were significantly down-regulated in miR-206 overexpressing BMSCs. We observed that significantly increased glutamine uptake at days 7 and 14 during the osteogenic induction and inhibition of glutamine metabolism by knocking down glutaminase (GLS)-suppressed osteogenic differentiation of BMSCs. Here, we discover that miR-206 could directly bind to the 3′-UTR region of GLS mRNA, resulting in suppressed GLS expression and glutamine metabolism. Finally, restoration of GLS in miR-206 overexpressing BMSCs led to recovery of glutamine metabolism and osteogenic differentiation. In summary, these results reveal a new insight into the mechanisms of the miR-206-mediated osteogenesis through regulating glutamine metabolism. Our study may contribute to the development of therapeutic agents against bone diseases.

An Update on the Progress of Isolation, Culture, Storage, and Clinical Application of Human Bone Marrow Mesenchymal Stem/Stromal Cells

“…The authors identified 17 miRNAs that were upregulated and five miRNAs were downregulated, which target various genes during osteoblast differentiation when compared to undifferentiated BMSCs [107]. These findings were consistent with the findings of Ying Chen et al [108]. Moreover, a balanced differentiation of BMSCs also contributes to hematopoietic recovery after bone marrow transplantation [109].…”

Downregulation of MicroRNA-206 Alleviates the Sublethal Oxidative Stress-Induced Premature Senescence and Dysfunction in Mesenchymal Stem Cells via Targeting Alpl

“…Specifically, miR-206 was upregulated in MSCs under hypoxic condition, and inhibition of miR-206 had antiapoptotic and migration-promoting effects on MSCs [32]. Later, Chen et al reported that miR-206 could inhibit the osteogenic differentiation of MSCs by targeting glutaminase [33]. Recently, miR-206 was reported downregulated in response to oxidative stress in cardiomyocytes and I/R in the heart, and exogenous miR-206 expression could reduce injury whereas endogenous miR-206 could promote survival of cardiomyocytes during I/R [10].…”

Glutamine Metabolism Is Essential for Stemness of Bone Marrow Mesenchymal Stem Cells and Bone Homeostasis

“…Alternatively, miRNA as an important regulator was able to establish a complex circuit in bone homeostasis by interacting with different genes [64]. Recent evidences reported that miRNA-206 participated BMSC bioenergy by directly bounding to the 3′-untranslated region (3′-UTR) of GLS mRNA, which resulted in the suppression of GLS expression and glutamine metabolism and eventually inhibited the osteogenic differentiation of BMSCs [65].…”