ShRNA-MEDIATED KNOCKDOWN OF INTERLEUKIN-6 EXPRESSION RESCUES TUMOR NECROSIS FACTOR α-INHIBITED OSTEOGENESIS IN MOUSE MESENCHYMAL PRECURSOR CELLS
DOI: http://dx.doi.org/10.30970/sbi.0903.456
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-1β), 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 TNFα 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 pathways 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 IL-6 mRNA significantly increased early hBMP2/7-induced osteogenesis and rescues it from the negative effect of TNFα in C2C12 cells. It also intensified bone matrix mineralization in KS483 mouse mesenchymal precursor cells (MPC). Thus, IL-6 is an important mediator in the inhibition of osteoblast differentiation by the TNFα, 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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