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Premise and peril of Wnt signaling activation through GSK-3β inhibition.

ABSTRACT: Wnt signaling pathways have been extensively studied in the context of several diseases, including cancer, coronary artery disease, and age-related disorders. β-Catenin plays a central role in the most studied Wnt pathways, the Wnt/β-catenin signaling pathway, commonly referred to as the canonical Wnt signaling pathway. β-catenin is a substrate of glycogen synthase kinase 3β (GSK-3β), and the phosphorylated β-catenin by GSK-3β can be degraded by the proteasome through ubiquitination. Thus, GSK-3β inhibitors have become a widely used chemical biology tool to study the canonical Wnt signaling pathway. Among the varied GSK-3β inhibitors, a compound known as CHIR-99021 is one of the most widely used. Although these inhibitors contribute greatly to our understanding of the canonical Wnt pathway, certain pitfalls associated with such an approach may have been overlooked. In many published studies, micromolar concentrations of CHIR-99021 are used to activate the canonical Wnt pathway. Although CHIR-99021 is a specific GSK-3β inhibitor, it specifically inhibits the kinase at the nanomolar level. Therefore, caution is required when micromolar levels of CHIR-99021 are used for the purpose of activating the canonical Wnt signaling pathway.

SUBMITTER: Law SM

PROVIDER: S-EPMC9010644 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Premise and peril of Wnt signaling activation through GSK-3β inhibition.

Law Samuel M SM Zheng Jie J JJ

iScience 20220325 4

Wnt signaling pathways have been extensively studied in the context of several diseases, including cancer, coronary artery disease, and age-related disorders. β-Catenin plays a central role in the most studied Wnt pathways, the Wnt/β-catenin signaling pathway, commonly referred to as the canonical Wnt signaling pathway. β-catenin is a substrate of glycogen synthase kinase 3β (GSK-3β), and the phosphorylated β-catenin by GSK-3β can be degraded by the proteasome through ubiquitination. Thus, GSK-3 ...[more]

PMID: 35434563

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Project description:Small-molecule-inhibitor-based bone differentiation has been recently exploited as a novel approach to regulating osteogenesis-related signaling pathways. In this study, we identified 1-Azakenpaullone, a highly selective inhibitor of glycogen synthase kinase-3β (GSK-3β), as a powerful inducer of osteoblastic differentiation and mineralization of human mesenchymal stem cells (MSCs). GSK-3β is a serine-threonine protein kinase that plays a major role in different disease development. GSK-3β is a key regulator of Runx2 activity in osteoblastic formation. We evaluated alkaline phosphatase activity and staining assays to assess osteoblast differentiation and Alizarin Red staining to assess the mineralization of cultured human MSCs. Gene expression profiling was assessed using an Agilent microarray platform, and bioinformatics were performed using Ingenuity Pathway Analysis software. Human MSCs treated with 1-Azakenpaullone showed higher ALP activity, increased in vitro mineralized matrix formation, and the upregulation of osteoblast-specific marker gene expression. Global gene expression profiling of 1-Azakenpaullone-treated human MSCs identified 1750 upregulated and 2171 downregulated mRNA transcripts compared to control cells. It also suggested possible changes in various signaling pathways, including Wnt, TGFβ, and Hedgehog. Further bioinformatics analysis employing Ingenuity Pathway Analysis recognized significant enrichment in the 1-Azakenpaullone-treated cells of genetic networks involved in CAMP, PI3K (Complex), P38 MAPK, and HIF1A signaling and functional categories associated with connective tissue development. Our results suggest that 1-Azakenpaullone significantly induced the osteoblastic differentiation and mineralization of human MSCs mediated by the activation of Wnt signaling and the nuclear accumulation of β-catenin, leading to the upregulation of Runx2, a key transcription factor that ultimately promotes the expression of osteoblast-specific genes. Thus, 1-Azakenpaullone could be used as an osteo-promotor factor in bone tissue engineering.

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Premise and peril of Wnt signaling activation through GSK-3β inhibition.

Publications

Premise and peril of Wnt signaling activation through GSK-3β inhibition.

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