The most important aspects of stem cell therapy are improving the microenvironment, cell homing and continuous factor stimulation. Stem cells have already been proven to have a high potential for angiogenesis. This is the first report identifying the involvement of NPR3-mediated MAPK pathway in the metformin-enhanced osteogenic differentiation, indicating that NPR3 antagonists, such as metformin, may be feasible therapeutics for periodontal tissue regeneration in diabetic individuals.Ī lack of angiogenesis is the key problem in the healing of diabetic foot ulcers. The present study suggests that metformin may enhance the osteogenic differentiation of PDLSCs under high glucose via downregulation of NPR3 and inhibition of its downstream MAPK pathway. When the underlying pathways involved were investigated, we found that upregulation of NPR3 can compromise the metformin-enhanced PDLSC osteogenic differentiation and activate the MAPK pathway (especially the p38 MAPK and Erk1/2 pathway), and that inhibition of the NPR3-mediated p38 MAPK or Erk1/2 pathway enhanced the osteogenic differentiation of PDLSCs under high glucose. Furthermore, the results of RNA-seq analysis showed that natriuretic peptide receptor 3 (NPR3) was upregulated in PDLSCs under high glucose and downregulated after metformin addition. We found that osteogenic differentiation of PDLSCs under high glucose was decreased, and metformin addition enhanced this capacity of differentiation. Western blot analysis was also used to detect the protein level of underlying signaling pathways. RNA-seq analysis was performed to screen target genes of metformin, and the effects of target genes were confirmed using lentivirus transfection. Osteogenic differentiation of PDLSCs was assessed by alkaline phosphatase (ALP) staining, ALP activity, Alizarin Red staining and quantitative assay, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. However, how metformin combats damage to PDLSC osteogenic differentiation under high glucose and the underlying mechanisms remain unknown. Metformin is an anti-hyperglycemic drug that exhibits abundant biological activities associated with cell metabolism and downstream tissue regeneration. High glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) has long been a challenge to periodontal regeneration for diabetic individuals. These findings suggest that morroniside attenuates HG‐mediated BMSC dysfunction partly through the inhibition of AGE‐RAGE signalling and activation of Glo1 and may be a potential treatment for diabetic osteoporosis. Furthermore, in vivo, morroniside attenuated bone loss and improved bone microarchitecture accompanied by Glo1 upregulation and RAGE downregulation. Moreover, the enhanced osteogenesis due to morroniside treatment was partially blocked by the Glo1 inhibitor, BBGCP2. Morroniside suppressed advanced glycation end product (AGEs) formation and RAGE expression by triggering Glo1. Morroniside treatment reverses the HG‐impaired osteogenic differentiation of BMSCs in vitro. Additionally, a T1DM rat model was used to assess the protective effect of morroniside in vivo. Quantitative real‐time PCR and Western blot (WB) were used to investigate the osteo‐specific markers, receptor for advanced glycation end product (RAGE) signalling and glyoxalase‐1 (Glo1). However, the effects and underlying mechanisms of morroniside on HG‐induced BMSC dysfunction remain poorly understood.Īlkaline phosphatase (ALP) staining, ALP activity and Alizarin Red staining were performed to assess the osteogenesis of BMSCs. Morroniside is an iridoid glycoside derived from the Chinese herb Cornus officinalis, and it has abundant biological activities associated with cell metabolism and tissue regeneration. High glucose (HG)–mediated bone marrow mesenchymal stem cell (BMSC) dysfunction plays a key role in impaired bone formation induced by type 1 diabetes mellitus (T1DM).
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