Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation

Tsukazaki, Hiroyuki; Kikuta, Junichi; Ao, Tomoka; Morimoto, Akito; Fukuda, Chie; Tsuda, Eisuke; Minoshima, Masafumi; Kikuchi, Kazuya; Kaito, Takashi; Ishii, Masaru

doi:https://doi.org/10.1016/j.bone.2021.116095

Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation

Tsukazaki, Hiroyuki; Kikuta, Junichi; Ao, Tomoka et al.

Bone, 2021, 152, 116095

Number of Access:1,348（2025-07-24 02:15 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/93157

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Title	Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation
Creator	CreatorName Tsukazaki, Hiroyuki
	NRID 1000060710069 1000060710069 researchmap permalink jkikuta jkikuta Scopus Author ID 36637603800 36637603800 CreatorName Kikuta, Junichi
	NRID 1000090880865 1000090880865 researchmap permalink tomoka_ao1203 tomoka_ao1203 CreatorName Ao, Tomoka
	NRID 1000010881740 1000010881740 Scopus Author ID 57200327474 57200327474 CreatorName Morimoto, Akito
	CreatorName Fukuda, Chie
	CreatorName Tsuda, Eisuke
	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 1000070623982 1000070623982 ORCID 0000-0003-4882-2997 0000-0003-4882-2997 researchmap permalink 911_0 911_0 Scopus Author ID 25824322100 25824322100 CreatorName Kaito, Takashi
	NRID 1000010324758 1000010324758 researchmap permalink read0076684 read0076684 Scopus Author ID 35074093500 35074093500 CreatorName Ishii, Masaru
Subject	Anti-resorptive agent
	Bone coupling
	Osteoclast
	Osteoporosis
	Siglec-15
	Two-photon microscope
Description	Tsukazaki H., Kikuta J., Ao T., et al. Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation. Bone 152, 116095 (2021); https://doi.org/10.1016/j.bone.2021.116095.
Abstract	Anti-resorptive drugs are widely used for the treatment of osteoporosis, but excessive inhibition of osteoclastogenesis can suppress bone turnover and cause the deterioration of bone quality. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a transmembrane protein expressed on osteoclast precursor cells and mature osteoclasts. Siglec-15 regulates proteins containing immunoreceptor tyrosine-based activation motif (ITAM) domains, which then induce nuclear factor of activated T-cells 1 (NFATc1), a master transcription factor of osteoclast differentiation. Anti-Siglec-15 antibody modulates ITAM signaling in osteoclast precursors and inhibits the maturation of osteoclasts in vitro. However, in situ pharmacological effects, particularly during postmenopausal osteoporosis, remain unclear. Here, we demonstrated that anti-Siglec-15 antibody treatment protected against ovariectomy-induced bone loss by specifically inhibiting the generation of multinucleated osteoclasts in vivo. Moreover, treatment with anti-Siglec-15 antibody maintained bone formation to a greater extent than with risedronate, the first-line treatment for osteoporosis. Intravital imaging revealed that anti-Siglec-15 antibody treatment did not cause a reduction in osteoclast motility, whereas osteoclast motility declined following risedronate treatment. We evaluated osteoclast activity using a pH-sensing probe and found that the bone resorptive ability of osteoclasts was lower following anti-Siglec-15 antibody treatment compared to after risedronate treatment. Our findings suggest that anti-Siglec-15 treatment may have potential as an anti-resorptive therapy for osteoporosis, which substantially inhibits the activity of osteoclasts while maintaining physiological bone coupling.
Publisher	Elsevier Inc.
Source Title	Bone
Volume (Issue)	152
Page	116095
Date of Issued	2021-11-01
Language	English
Handle URL	https://hdl.handle.net/11094/93157
PISSN	87563282
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.bone.2021.116095
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	Bone. 2021, 152, p. 116095
DC.title	Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation
DC.creator	Tsukazaki, Hiroyuki
	Kikuta, Junichi
	Ao, Tomoka
	Morimoto, Akito
	Fukuda, Chie
	Tsuda, Eisuke
	Minoshima, Masafumi
	Kikuchi, Kazuya
	Kaito, Takashi
	Ishii, Masaru
DC.publisher	Elsevier Inc.
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2021-11-01
DC.identifier	https://doi.org/10.1016/j.bone.2021.116095
DC.subject	Anti-resorptive agent
	Bone coupling
	Osteoclast
	Osteoporosis
	Siglec-15
	Two-photon microscope
DC.description	Tsukazaki H., Kikuta J., Ao T., et al. Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation. Bone 152, 116095 (2021); https://doi.org/10.1016/j.bone.2021.116095.
DCTERMS.abstract	Anti-resorptive drugs are widely used for the treatment of osteoporosis, but excessive inhibition of osteoclastogenesis can suppress bone turnover and cause the deterioration of bone quality. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a transmembrane protein expressed on osteoclast precursor cells and mature osteoclasts. Siglec-15 regulates proteins containing immunoreceptor tyrosine-based activation motif (ITAM) domains, which then induce nuclear factor of activated T-cells 1 (NFATc1), a master transcription factor of osteoclast differentiation. Anti-Siglec-15 antibody modulates ITAM signaling in osteoclast precursors and inhibits the maturation of osteoclasts in vitro. However, in situ pharmacological effects, particularly during postmenopausal osteoporosis, remain unclear. Here, we demonstrated that anti-Siglec-15 antibody treatment protected against ovariectomy-induced bone loss by specifically inhibiting the generation of multinucleated osteoclasts in vivo. Moreover, treatment with anti-Siglec-15 antibody maintained bone formation to a greater extent than with risedronate, the first-line treatment for osteoporosis. Intravital imaging revealed that anti-Siglec-15 antibody treatment did not cause a reduction in osteoclast motility, whereas osteoclast motility declined following risedronate treatment. We evaluated osteoclast activity using a pH-sensing probe and found that the bone resorptive ability of osteoclasts was lower following anti-Siglec-15 antibody treatment compared to after risedronate treatment. Our findings suggest that anti-Siglec-15 treatment may have potential as an anti-resorptive therapy for osteoporosis, which substantially inhibits the activity of osteoclasts while maintaining physiological bone coupling.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	93157
citation_title	Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation
citation_author	Tsukazaki, Hiroyuki
	Kikuta, Junichi
	Ao, Tomoka
	Morimoto, Akito
	Fukuda, Chie
	Tsuda, Eisuke
	Minoshima, Masafumi
	Kikuchi, Kazuya
	Kaito, Takashi
	Ishii, Masaru
citation_publisher	Elsevier Inc.
citation_language	English
citation_date	2021-11-01
citation_journal_title	Bone
citation_volume	152
citation_firstpage	116095
citation_doi	https://doi.org/10.1016/j.bone.2021.116095
citation_public_url	https://hdl.handle.net/11094/93157

Anti-Siglec-15 antibody suppresses bone resorption by inhibiting osteoclast multinucleation without attenuating bone formation

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