Authors: Shoichi Kaneshiro Kosuke Ebina Kenrin Shi Chikahisa Higuchi Makoto Hirao Michio Okamoto Kota Koizumi Tokimitsu Morimoto Hideki Yoshikawa Jun Hashimoto
Publish Date: 2013/10/12
Volume: 32, Issue: 4, Pages: 378-392
Abstract
It has been suggested that interleukin6 IL6 plays a key role in the pathogenesis of rheumatoid arthritis RA including osteoporosis not only in inflamed joints but also in the whole body However previous in vitro studies regarding the effects of IL6 on osteoblast differentiation are inconsistent The aim of this study was to examine the effects and signal transduction of IL6 on osteoblast differentiation in MC3T3E1 cells and primary murine calvarial osteoblasts IL6 and its soluble receptor significantly reduced alkaline phosphatase ALP activity the expression of osteoblastic genes Runx2 osterix and osteocalcin and mineralization in a dosedependent manner which indicates negative effects of IL6 on osteoblast differentiation Signal transduction studies demonstrated that IL6 activated not only two major signaling pathways SHP2/MEK/ERK and JAK/STAT3 but also the SHP2/PI3K/Akt2 signaling pathway The negative effect of IL6 on osteoblast differentiation was restored by inhibition of MEK as well as PI3K while it was enhanced by inhibition of STAT3 Knockdown of MEK2 and Akt2 transfected with siRNA enhanced ALP activity and gene expression of Runx2 These results indicate that IL6 negatively regulates osteoblast differentiation through SHP2/MEK2/ERK and SHP2/PI3K/Akt2 pathways while affecting it positively through JAK/STAT3 Inhibition of MEK2 and Akt2 signaling in osteoblasts might be of potential use in the treatment of osteoporosis in RA
Keywords: