Malysheva K. Wnt signaling pathway inhibition by interleukin 6 and its role in the development and progression of rheumatoid arthritis

The thesis is devoted to the study of the negative regulatory influence of interleukin 6 (IL-6) and PTTG1/PTTG-BP1 axis on activation of Wnt signaling pathway and consequently osteoblastic differentiation of mouse mesenchymal stem cells (MSC), its role in the development and progression of RA. It was firstly shown that IL-6 inhibited the activation of Wnt signaling in primary human synoviocytes, and, together with tumor necrosis factor (TNF) and DKK-1, inhibited the activation of Wnt response. Small hairpin (sh) RNA-mediated knockdown of IL-6 mRNA significantly increased early bone morphogenetic proteins (BMP2/7)-induced osteogenesis and rescued it from the negative effect of TNF, as well as intensified bone matrix mineralization in mouse MSC. It was found that ectopic expression of pttg1 gene inhibited BMP2/7-induced osteogenenic differentiation and bone matrix mineralization in mouse MCS. At the same time shRNA-mediated knockdown of mRNA pttg1 gene led to a substantial activation of bone formation in these cells. The treatment of mouse MCS with novel 4-thiazolidinone-based derivatives denoted as Les-4368 and Les-3882 rescued the osteoblast differentiation from negative control of TNF, and, moreover, converted this cytokine from the inhibitor of osteogenesis into its stimulator. We found that the most effective inducer of osteoblast differentiation was recombinant BMP preparation produced upon co-transfection of 85 of BMP2 and 15 % of BMP7 plasmids.