JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors

Yari, Shinya; Kikuta, Junichi; Shigyo, Hotaka; Miyamoto, Yu; Okuzaki, Daisuke; Furusawa, Yuki; Minoshima, Masafumi; Kikuchi, Kazuya; Ishii, Masaru

doi:https://doi.org/10.1186/s41232-023-00268-4

JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors

Yari, Shinya; Kikuta, Junichi; Shigyo, Hotaka et al.

Inflammation and Regeneration, 2023, 43(1), 18

Number of Access:1,604（2025-09-29 18:20 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/93151

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Title	JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors
Creator	CreatorName Yari, Shinya
	NRID 1000060710069 1000060710069 researchmap permalink jkikuta jkikuta Scopus Author ID 36637603800 36637603800 CreatorName Kikuta, Junichi
	CreatorName Shigyo, Hotaka
	NRID 1000090965336 1000090965336 researchmap permalink yumiyamoto yumiyamoto ORCID 0000-0002-2715-6465 0000-0002-2715-6465 CreatorName Miyamoto, Yu
	NRID 1000000346131 1000000346131 ORCID 0000-0002-4552-783X 0000-0002-4552-783X researchmap permalink read0092307 read0092307 Scopus Author ID 6506703054 6506703054 CreatorName Okuzaki, Daisuke
	CreatorName Furusawa, Yuki
	NRID 1000020600844 1000020600844 ORCID 0000-0002-9352-3454 0000-0002-9352-3454 researchmap permalink cbatgcm_m33 cbatgcm_m33 Scopus Author ID 12774750700 12774750700 CreatorName Minoshima, Masafumi
	NRID 1000070292951 1000070292951 researchmap permalink kikuchilab315 kikuchilab315 Scopus Author ID 7404088901 7404088901 CreatorName Kikuchi, Kazuya
	NRID 1000010324758 1000010324758 researchmap permalink read0076684 read0076684 Scopus Author ID 35074093500 35074093500 CreatorName Ishii, Masaru
Subject	Cell migration
	Chemokine
	Inflammatory bone destruction
	Intravital imaging
	JAK inhibitor
	Osteoclast
Description	Yari S., Kikuta J., Shigyo H., et al. JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors. Inflammation and Regeneration 43, 18 (2023); https://doi.org/10.1186/s41232-023-00268-4.
Abstract	Background: Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging. Methods: Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts. Results: The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions. Conclusions: This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.
Publisher	BioMed Central Ltd
Source Title	Inflammation and Regeneration
Volume (Issue)	43(1)
Page	18
Date of Issued	2023-03-03
Language	English
Handle URL	https://hdl.handle.net/11094/93151
eISSN	18808190
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1186/s41232-023-00268-4
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Inflammation and Regeneration. 2023, 43(1), p. 18
DC.title	JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors
DC.creator	Yari, Shinya
	Kikuta, Junichi
	Shigyo, Hotaka
	Miyamoto, Yu
	Okuzaki, Daisuke
	Furusawa, Yuki
	Minoshima, Masafumi
	Kikuchi, Kazuya
	Ishii, Masaru
DC.publisher	BioMed Central Ltd
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2023-03-03
DC.identifier	https://doi.org/10.1186/s41232-023-00268-4
DC.subject	Cell migration
	Chemokine
	Inflammatory bone destruction
	Intravital imaging
	JAK inhibitor
	Osteoclast
DC.description	Yari S., Kikuta J., Shigyo H., et al. JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors. Inflammation and Regeneration 43, 18 (2023); https://doi.org/10.1186/s41232-023-00268-4.
DCTERMS.abstract	Background: Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging. Methods: Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts. Results: The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions. Conclusions: This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	93151
citation_title	JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors
citation_author	Yari, Shinya
	Kikuta, Junichi
	Shigyo, Hotaka
	Miyamoto, Yu
	Okuzaki, Daisuke
	Furusawa, Yuki
	Minoshima, Masafumi
	Kikuchi, Kazuya
	Ishii, Masaru
citation_publisher	BioMed Central Ltd
citation_language	English
citation_date	2023-03-03
citation_journal_title	Inflammation and Regeneration
citation_volume	43
citation_issue	1
citation_firstpage	18
citation_doi	https://doi.org/10.1186/s41232-023-00268-4
citation_public_url	https://hdl.handle.net/11094/93151

JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors

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