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  • Title: Notch signaling represses hypoxia-inducible factor-1α-induced activation of Wnt/β-catenin signaling in osteoblasts under cobalt-mimicked hypoxia.
    Author: Li CT, Liu JX, Yu B, Liu R, Dong C, Li SJ.
    Journal: Mol Med Rep; 2016 Jul; 14(1):689-96. PubMed ID: 27220406.
    Abstract:
    The modification of Wnt and Notch signaling pathways by hypoxia, and its association with osteoblast proliferation and apoptosis remain to be fully elucidated. To investigate Wnt-Notch crosstalk, and its role in hypoxia-induced osteoblast proliferation and apoptosis regulation, the present study investigated the effects of cobalt‑mimicked hypoxia on the mouse pre-osteoblast-like cell line, MC3T3‑E1, when the Notch signals were repressed using a γ‑secretase inhibitor DAPT. The data showed that the cobalt‑mimicked hypoxia suppressed cell proliferation under normal conditions, but increased cell proliferation under conditions of Notch repression, in a concentration‑dependent manner. The results of western blot and reverse transcription‑quantitative polymerase chain reaction analyses showed that the cobalt treatment increased the levels of activated β‑catenin protein and the expression levels of the target genes, axis inhibition protein 2 and myelocytomatosis oncogene, under DAPT‑induced Notch repression. However, no significant changes were found in the expression levels of the Notch intracellular domain protein or the Notch target gene, hes1. In a β‑catenin gene‑knockdown experiment, the proliferation of the MC3T3‑E1 cells under hypoxia were decreased by DAPT treatment, and knockdown of the expression of hypoxia‑inducible factor‑1α (HIF‑1α) suppressed the cobalt‑induced increase in Wnt target gene levels. No significant difference in cell proliferation rate was found following DAPT treatment when the expression of HIF‑1α was knocked down. The results of the present study showed the opposing effects of Wnt and Notch signaling under cobalt‑mimicked hypoxia, which were partially regulated by HIF‑1α, The results also showed that osteoblast proliferation was dependent on Wnt-Notch signal crosstalk.
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