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.