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.
Highlights
MiRNAs are non-coding, single-stranded, and short (22–24 nts) RNAs that post-transcriptionally regulate the gene expression by binding to the 3 -UTR of their target mRNAs [1]. miRNAs play important roles in a variety of cellular processes including proliferation, migration, differentiation, and apoptosis [2]
Previous findings revealed that osteogenic differentiation of bone marrow mesenchymal stem cell (BMSC) is post-transcriptionally regulated by miRNAs [14]
To understand whether miR-206 is involved in osteogenic differentiation of BMSCs, we investigated the pattern of miR-206 expression during the osteogenic differentiation
Summary
MiRNAs are non-coding, single-stranded, and short (22–24 nts) RNAs that post-transcriptionally regulate the gene expression by binding to the 3 -UTR of their target mRNAs [1]. miRNAs play important roles in a variety of cellular processes including proliferation, migration, differentiation, and apoptosis [2]. MiRNAs play important roles in a variety of cellular processes including proliferation, migration, differentiation, and apoptosis [2]. MiRNAs are involved in the diverse pathology of human bone diseases [3,4]. Osteoblast-mediated bone formation is a complex but finely orchestrated process [6]. One of the important regulators of bone formation is the bone morphogenetic protein (BMP), which plays major roles during the osteoblast lineage-specific differentiation, and later, in bone formation [7]. Bone marrow mesenchymal stem cells (BMSCs) are the progenitor cells for osteoblasts, adipocytes, and chondrocytes [8]. The potential of BMSCs to differentiate into osteoblasts or adipocytes can be utilized to repair and reconstruct bone tissue injury or disease [9], providing a potential strategy for clinical treatments.
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