ShRNA-mediated knockdown of interleukin-6 expression rescues tumor necrosis factor α-inhibited osteogenesis in mouse mesenchymal precursor cells
Journal: Біологічні Студії Studia Biologica (Vol.9, No. 34)Publication Date: 2015-12-02
Authors : Kh. V. Malysheva; K. de Rooij; C. W. G. M. L.wik; D. L. Baeten; R. S. Stoika; O. G. Korchynskyi;
Page : 5-15
Keywords : rheumatoid arthritis; interleukin-6; osteogenesis; mesenchymal stem cells; Wnt signaling pathway;
Abstract
Rheumatoid arthritis (RA) is a severe autoimmune inflammatory disorder that strongly reduces a quality of patient’s life due to its association with different morbidities and socioeconomic expenses.The etiology of the disease remains unknown. It has been demonstrated that interleukin-6 (IL-6), a target gene of tumor necrosis factor α(TNFα) and interleukin 1β (IL-1b), plays a crucial role in the pathophysiology of RA. It is well known that bone morphogenetic protein (BMP)- and Wnt-involved pathways are key signaling mechanisms that induce and potentiate cartilage and bone formation and maintenance. We found that IL-6 similarly to TNF α inhibits activation of Wnt signaling pathway in primary human synoviocytes. In current study, we evaluated an impact of previously unrecognized negative interaction between the Wnt and IL-6 signaling path- ways in skeletal tissues, as a possible major mechanism leading to age- and inflammation-related bone and joints destruction. It was found that shRNA-mediated knockdown of IL6 mRNA significantly increased early hBMP2 /7-induced osteogenesis and rescues it from the negative effect of TNF α in C2C12 cells. It also intensified bone matrix mineralization in KS483 mouse mesenchymal precursor cells (MPC). Thus, IL-6 is an important mediator of the inhibition of osteoblast differentiation by the TNF α, and knockdown of IL-6 expression partially rescues osteogenesis from the negative control of inflammation. The anti-osteoblastic effects of IL-6 are most likely mediated by its negative regulation of Wnt signaling pathway
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