Interleukin 6/Wnt interactions in rheumatoid arthritis: interleukin 6 inhibits Wnt signaling in synovial fibroblasts and osteoblasts.
OBJECTIVE
To evaluate the impact of previously unrecognized negative interaction between the Wnt and interleukin (IL) 6 signaling pathways in skeletal tissues as a possible major mechanism leading to age- and inflammation-related destruction of bone and joints.


METHODS
Luciferase reporter assays were performed to monitor Wnt pathway activation upon IL-6 and tumor necrosis factor-α (TNFα) treatment. Functional contribution of IL-6 and TNFα interaction to inhibition of bone formation was evaluated in vitro using small hairpin RNAs (shRNA) in mouse mesenchymal precursor cells (MPC) of C2C12 and KS483 lines induced to differentiate into osteoblasts by bone morphogenetic proteins (BMP).


RESULTS
IL-6 inhibited the activation of Wnt signaling in primary human synoviocytes, and, together with TNFα and Dickkopf-1, inhibited the activation of Wnt response. ShRNA-mediated knockdown of IL-6 mRNA significantly increased early BMP2/7-induced osteogenesis and rescued it from the negative effect of TNFα in C2C12 cells, as well as intensified bone matrix mineralization in KS483 cells.


CONCLUSIONS
IL-6 is an important mediator in the inhibition of osteoblast differentiation by TNFα, and knockdown of IL-6 partially rescues osteogenesis from the negative control of inflammation. The anti-osteoblastic effects of IL-6 are most likely mediated by its negative interaction with Wnt signaling pathway.
Khrystyna
K
Malysheva
Karien
K
de Rooij
Clemens Wgm
CW
Lowik
Dominique L
DL
Baeten
Stefan
S
Rose-John
Rostyslav
R
Stoika
Olexandr Korchynskyi, Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology of the National Academy of Sciences of Ukraine (NASU), 14/16, Drahomanov St., Lviv 79005, Ukraine, olexkor@hotmail.com.
Olexandr
O
Korchynskyi
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
D019485:Bone Morphogenetic Proteins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins