Abstract
BackgroundMesenchymal stem cells (MSCs) play a crucial role in maintaining the dynamic balance of bone metabolism. Melatonin may have a regulatory effect on bone metabolism by regulating the lineage commitment and differentiation signalling pathways of MSCs. Among the BMP families, the osteogenesis of BMP9 is considered to be one of the strongest in MSCs. Here, we explored whether melatonin and BMP9 act synergistically on MSC osteogenic differentiation.MethodsThe C3H10T1/2 osteogenic differentiation function induced by melatonin synergizes with BMP9, as detected by the expression of osteogenic markers at different periods. The result was further confirmed by foetal limb explant culture and in vivo stem cell implantation experiments. The effects of the AMPK/β-catenin pathway on the osteogenic differentiation of C3H10T1/2 cells were evaluated by Western blotting.ResultsMelatonin combined with BMP9 significantly enhanced the expression of osteogenic markers at different periods in C3H10T1/2 cells, effectively enhancing BMP9-induced bone formation in cultured foetal explants and ectopic bone formation in vivo in stem cell transplantation experiments. Melatonin increases the expression of BMP9 in C3H10T1/2 cells and induces Smad1/5/8 translocation from the cytoplasm to the nucleus. In addition, melatonin and BMP9 synergistically promote AMPK and β-catenin phosphorylation, which can be largely eliminated by AMPK siRNA pretreatment.ConclusionsMelatonin and BMP9 in C3H10T1/2 cells synergistically promote osteogenic differentiation at least in part by activating the AMPK/β-catenin signalling pathway.
Highlights
Mesenchymal stem cells (MSCs) play a crucial role in maintaining the dynamic balance of bone metabolism
Melatonin synergizes with Bone morphogenetic protein-9 (BMP9) to induce the Alkaline phosphatase (ALP) activity of C3H10T1/2 cells To explore the effects of melatonin and BMP9 in synergistically inducing the osteogenic differentiation of MSC/ C3H10T1/2 s, we used a recombinant adenovirus expressing human BMP9 as described above and demonstrated that this recombinant adenovirus is capable of efficiently transducing C3H10T1/2 cells (Fig. 1a)
The results indicate that melatonin can synergize with BMP9 to induce the osteogenic differentiation of C3H10T1/2 cells through the AMPK/βcatenin pathway
Summary
Mesenchymal stem cells (MSCs) play a crucial role in maintaining the dynamic balance of bone metabolism. The osteogenic differentiation of MSCs plays an important role in bone regeneration and remodelling. This process is regulated by a variety of hormones, transcription factors and cellular signalling pathways, including bone morphogenetic protein (BMP), Wnt, insulin-like growth factor (IGF), epidermal growth factor and growth hormone, and is involved in multiple pathway interactions [3,4,5,6]. Bone morphogenetic proteins (BMPs) are important signalling pathways for cell proliferation and differentiation during embryonic development and play a key role in regulating the osteogenic differentiation of mesenchymal stem cells [7]. BMPs belong to the transforming growth factor (TGF) superfamily and have at least 15
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