COMPARATIVE STUDY
JOURNAL ARTICLE

Effects of vascular endothelial cells on osteogenic differentiation of noncontact co-cultured periodontal ligament stem cells under hypoxia

Y Wu, H Cao, Y Yang, Y Zhou, Y Gu, X Zhao, Y Zhang, Z Zhao, L Zhang, J Yin
Journal of Periodontal Research 2013, 48 (1): 52-65
22905750

BACKGROUND AND OBJECTIVE: During periodontitis or orthodontic tooth movement, the periodontal vasculature is severely impaired by chronic inflammation or excessive mechanical force. This leads to a hypoxic microenvironment of the periodontal cells and enhances the expression of various cytokines and growth factors that may regulate angiogenesis and alveolar bone remodeling. However, the role of hypoxia in regulating the communication between endothelial cells (ECs) and osteoblast progenitors during the remodeling and repair of periodontal tissue is still poorly defined. The aim of this study was to investigate the effects of vascular ECs on osteogenic differentiation, mineralization and the paracrine function of noncontact co-cultured periodontal ligament stem cells (PDLSCs) under hypoxia, and further reveal the involvement of MEK/ERK and p38 MAPK pathways in the process.

MATERIAL AND METHODS: First, PDLSCs were obtained and a noncontact co-culture system of PDLSCs and human umbilical vein endothelial cells was established. Second, the effects of different time-periods of hypoxia (2% O(2) ) on the osteogenic potential, mineralization and paracrine function of co-cultured PDLSCs were investigated. Third, ERK1/2 and p38 MAPK activities of PDLSCs under hypoxia were measured by western blotting. Finally, we employed specific MAPK inhibitors (PD98059 and SB20350) to investigate the involvement of ERK1/2 and p38 MAPK in PDLSC osteogenesis under hypoxia.

RESULTS: We observed further increased osteogenic differentiation of co-cultured PDLSCs, manifested by markedly enhanced alkaline phosphatase (ALP) activity and prostaglandin E(2) (PGE(2)) levels, vascular endothelial growth factor (VEGF) release, runt-related transcription factor 2 (Runx2) and Sp7 transcriptional and protein levels and mineralized nodule formation, compared with PDLSCs cultured alone. ERK1/2 was phosphorylated in a rapid but transient manner, whereas p38 MAPK was activated in a slow and sustained way under hypoxia. Furthermore, hypoxia-stimulated transcription and expression of osteogenic regulators (hypoxia-inducible factor-1α, ALP, Runx2, Sp7, PGE(2) and VEGF) were also inhibited by PD98059 and SB203580 to different degrees.

CONCLUSION: Further increased osteogenic differentiation and mineralization of co-cultured PDLSCs under hypoxia were regulated by MEK/ERK and p38 MAPK pathways. And the ECs-mediated paracrine of PGE(2) and VEGF may facilitate the unidirectional PDLSC-EC communication and promote PDLSCs osteogenesis.

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