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01.07.2014 | Original Article

IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro

verfasst von: Shoichi Kaneshiro, Kosuke Ebina, Kenrin Shi, Chikahisa Higuchi, Makoto Hirao, Michio Okamoto, Kota Koizumi, Tokimitsu Morimoto, Hideki Yoshikawa, Jun Hashimoto

Erschienen in: Journal of Bone and Mineral Metabolism | Ausgabe 4/2014

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Abstract

It has been suggested that interleukin-6 (IL-6) 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 IL-6 on osteoblast differentiation are inconsistent. The aim of this study was to examine the effects and signal transduction of IL-6 on osteoblast differentiation in MC3T3-E1 cells and primary murine calvarial osteoblasts. IL-6 and its soluble receptor significantly reduced alkaline phosphatase (ALP) activity, the expression of osteoblastic genes (Runx2, osterix, and osteocalcin), and mineralization in a dose-dependent manner, which indicates negative effects of IL-6 on osteoblast differentiation. Signal transduction studies demonstrated that IL-6 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 IL-6 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 IL-6 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.

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Titel: IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro
verfasst von: Shoichi Kaneshiro
Kosuke Ebina
Kenrin Shi
Chikahisa Higuchi
Makoto Hirao
Michio Okamoto
Kota Koizumi
Tokimitsu Morimoto
Hideki Yoshikawa
Jun Hashimoto
Publikationsdatum: 01.07.2014
Verlag: Springer Japan
Erschienen in: Journal of Bone and Mineral Metabolism / Ausgabe 4/2014
Print ISSN: 0914-8779
Elektronische ISSN: 1435-5604
DOI: https://doi.org/10.1007/s00774-013-0514-1

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IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro

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