Nitric Oxide Mediates Crosstalk between Interleukin 1β and WNT Signaling in Primary Human Chondrocytes by Reducing DKK1 and FRZB Expression

• Published in: International journal of molecular sciences 2017-11, Vol.18 (11), p.2491
• Main Authors: Zhong, Leilei, Schivo, Stefano, Huang, Xiaobin, Leijten, Jeroen, Karperien, Marcel, Post, Janine N
• Format: Article
• Language: English
• Subjects: Antagonists; Apoptosis; Arthritis; beta Catenin - metabolism; Biocompatibility; Biomedical materials; Cartilage; cell signaling; Chondrocytes; Chondrocytes - metabolism; computational modeling; Computer applications; Crosstalk; Cytokines; Dkk1 protein; Frizzled protein; Gene Expression Regulation; Glycoproteins - genetics; Heparan sulfate; Human behavior; Humans; IL1β; Inflammation; Inflammatory response; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin 1; Interleukin-1beta - metabolism; Interleukin-1beta - pharmacology; Matrix metalloproteinase; Metalloproteinase; Molecular biology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Osteoarthritis; Pathogenesis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription; WNT; Wnt protein; Wnt Signaling Pathway
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18112491

Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeling and molecular biology to reveal direct or indirect crosstalk between these pathways. Specifically, we revealed a mechanism by which IL1β upregulates WNT signaling via downregulating WNT antagonists, DKK1 and FRZB. In human chondrocytes, IL1β decreased the expression of Dickkopf-1 (DKK1) and Frizzled related protein (FRZB) through upregulation of nitric oxide synthase (iNOS), thereby activating the transcription of WNT target genes. This effect could be reversed by iNOS inhibitor 1400W, which restored DKK1 and FRZB expression and their inhibitory effect on WNT signaling. In addition, 1400W also inhibited both the matrix metalloproteinase (MMP) expression and cytokine-induced apoptosis. We concluded that iNOS/NO play a pivotal role in the inflammatory response of human OA through indirect upregulation of WNT signaling. Blocking NO production may inhibit the loss of the articular phenotype in OA by preventing downregulation of the expression of DKK1 and FRZB.