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

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

doi:https://doi.org/10.1007/s00774-013-0514-1

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

Kaneshiro, Shoichi; Ebina, Kosuke; Shi, Kenrin et al.

Journal of Bone and Mineral Metabolism, 2014, 32(4), 378-392

Number of Access:824（2025-09-03 11:38 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/93259

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Title	IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro
Creator	CreatorName Kaneshiro, Shoichi
	NRID 1000070612076 1000070612076 researchmap permalink k-ebina k-ebina Scopus Author ID 8415453300 8415453300 ORCID 0000-0002-2426-1024 0000-0002-2426-1024 CreatorName Ebina, Kosuke
	CreatorName Shi, Kenrin
	CreatorName Higuchi, Chikahisa
	NRID 1000010527708 1000010527708 CreatorName Hirao, Makoto
	CreatorName Okamoto, Michio
	CreatorName Koizumi, Kota
	CreatorName Morimoto, Tokimitsu
	NRID 1000060191558 1000060191558 CreatorName Yoshikawa, Hideki
	NRID 1000040237938 1000040237938 CreatorName Hashimoto, Jun
Subject	Akt2
	Interleukin-6
	MEK2
	Osteoblast differentiation
	Signaling pathway
Description	This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00774-013-0514-1
Description	Kaneshiro S., Ebina K., Shi K., et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. Journal of Bone and Mineral Metabolism 32, 378 (2014); https://doi.org/10.1007/s00774-013-0514-1.
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. © 2013 The Japanese Society for Bone and Mineral Research and Springer.
Publisher	Springer Nature
Source Title	Journal of Bone and Mineral Metabolism
Volume (Issue)	32(4)
Page	378-392
Date of Issued	2014-01-01
Language	English
Handle URL	https://hdl.handle.net/11094/93259
PISSN	09148779
eISSN	14355604
Relation.isVersionOf	DOI (Publisher Version) https://doi.org/10.1007/s00774-013-0514-1
Access Rights	open access
oaire:version	Accepted Manuscript
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Journal of Bone and Mineral Metabolism. 2014, 32(4), p. 378-392
DC.title	IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro
DC.creator	Kaneshiro, Shoichi
	Ebina, Kosuke
	Shi, Kenrin
	Higuchi, Chikahisa
	Hirao, Makoto
	Okamoto, Michio
	Koizumi, Kota
	Morimoto, Tokimitsu
	Yoshikawa, Hideki
	Hashimoto, Jun
DC.publisher	Springer Nature
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2014-01-01
DC.identifier	https://doi.org/10.1007/s00774-013-0514-1
DC.subject	Akt2
	Interleukin-6
	MEK2
	Osteoblast differentiation
	Signaling pathway
DC.description	This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00774-013-0514-1
DC.description	Kaneshiro S., Ebina K., Shi K., et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. Journal of Bone and Mineral Metabolism 32, 378 (2014); https://doi.org/10.1007/s00774-013-0514-1.
DCTERMS.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. © 2013 The Japanese Society for Bone and Mineral Research and Springer.
DC.format	93259
citation_title	IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro
citation_author	Kaneshiro, Shoichi
	Ebina, Kosuke
	Shi, Kenrin
	Higuchi, Chikahisa
	Hirao, Makoto
	Okamoto, Michio
	Koizumi, Kota
	Morimoto, Tokimitsu
	Yoshikawa, Hideki
	Hashimoto, Jun
citation_publisher	Springer Nature
citation_language	English
citation_date	2014-01-01
citation_journal_title	Journal of Bone and Mineral Metabolism
citation_volume	32
citation_issue	4
citation_firstpage	378
citation_lastpage	392
citation_doi	https://doi.org/10.1007/s00774-013-0514-1
citation_public_url	https://hdl.handle.net/11094/93259

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

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