Melatonin enhances osteogenic differentiation of dental pulp mesenchymal stem cells by regulating MAPK pathways and promotes the efficiency of bone regeneration in calvarial bone defects

Ya Hui Chan, Kuo Ning Ho, Yu Chieh Lee, Meng Jung Chou, Wei Zhen Lew, Haw Ming Huang, Pin Chuang Lai, Sheng Wei Feng

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


Background: Mesenchymal stem cell (MSC)-based tissue engineering plays a major role in regenerative medicine. However, the efficiency of MSC transplantation and survival of engrafted stem cells remain challenging. Melatonin can regulate MSC biology. However, its function in the osteogenic differentiation of dental pulp-derived MSCs (DPSCs) remains unclear. We investigated the effects and mechanisms of melatonin on the osteogenic differentiation and bone regeneration capacities of DPSCs. Methods: The biological effects and signaling mechanisms of melatonin with different concentrations on DPSCs were evaluated using a proliferation assay, the quantitative alkaline phosphatase (ALP) activity, Alizarin red staining, a real-time polymerase chain reaction, and a western blot in vitro cell culture model. The in vivo bone regeneration capacities were assessed among empty control, MBCP, MBCP + DPSCs, and MBCP + DPSCs + melatonin preconditioning in four-created calvarial bone defects by using micro-computed tomographic, histological, histomorphometric, and immunohistochemical analyses after 4 and 8 weeks of healing. Results: In vitro experiments revealed that melatonin (1, 10, and 100 μM) significantly and concentration-dependently promoted proliferation, surface marker expression (CD 146), ALP activity and extracellular calcium deposition, and osteogenic gene expression of DPSCs (p < 0.05). Melatonin activated the protein expression of ALP, OCN, and RUNX-2 and inhibited COX-2/NF-κB expression. Furthermore, the phosphorylation of mitogen-activated protein kinase (MAPK) p38/ERK signaling was significantly increased in DPSCs treated with 100 μM melatonin, and their inhibitors significantly decreased osteogenic differentiation. In vivo experiments demonstrated that bone defects implanted with MBCP bone-grafting materials and melatonin-preconditioned DPSCs exhibited significantly greater bone volume fraction, trabecular bone structural modeling, new bone formation, and osteogenesis-related protein expression than the other three groups at 4 and 8 weeks postoperatively (p < 0.05). Conclusions: These results suggest that melatonin promotes the proliferation and osteogenic differentiation of DPSCs by regulating COX-2/NF-κB and p38/ERK MAPK signaling pathways. Preconditioning DPSCs with melatonin before transplantation can efficiently enhance MSCs function and regenerative capacities.

Original languageEnglish
Article number73
JournalStem Cell Research and Therapy
Issue number1
Publication statusPublished - Dec 2022


  • Bone regeneration
  • Calvarial bone defect
  • COX2/NF-κB
  • Dental pulp mesenchymal stem cells
  • Melatonin
  • Osteogenesis
  • p38/ERK signaling pathway

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology


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