RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice

Kurihara, Takuya; Shimamura, Munehisa; Etani, Yuki; Noguchi, Takaaki; Fukuda, Yuji; Ochiai, Nagahiro; Goshima, Atsushi; Miura, Taihei; Hirao, Makoto; Sugimoto, Atsushi; Ju, Nan; Yamakawa, Satoshi; Kanamoto, Takashi; Nakata, Ken; Okada, Seiji; Ebina, Kosuke

doi:https://doi.org/10.1016/j.bone.2025.117440

RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice

Kurihara, Takuya; Shimamura, Munehisa; Etani, Yuki et al.

Bone, 2025, 194, 117440

Number of Access:236（2025-06-07 18:35 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100972

Link to primary information

File	Format	Terms of use	Size	Views	Date.Available	Description	information
Bone_194	pdf	None	11.5 MB	35	2025.04.15

Creative Commons : Attribution - NonCommercial - NoDerivatives

Item Information

Output File Export EndNote Basic Export Mendeley

Title	RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice
Creator	CreatorName Kurihara, Takuya
	NRID 1000060422317 1000060422317 researchmap permalink read8359 read8359 Scopus Author ID 7102059307 7102059307 CreatorName Shimamura, Munehisa
	NRID 1000060898930 1000060898930 ORCID 0000-0001-5741-5969 0000-0001-5741-5969 researchmap permalink Yetani0302 Yetani0302 CreatorName Etani, Yuki
	NRID 1000050812294 1000050812294 ORCID 0000-0001-9938-6780 0000-0001-9938-6780 researchmap permalink takaakinoguchi takaakinoguchi CreatorName Noguchi, Takaaki
	CreatorName Fukuda, Yuji
	CreatorName Ochiai, Nagahiro
	CreatorName Goshima, Atsushi
	CreatorName Miura, Taihei
	NRID 1000010527708 1000010527708 CreatorName Hirao, Makoto
	CreatorName Sugimoto, Atsushi
	CreatorName Ju, Nan
	NRID 1000040816740 1000040816740 researchmap permalink satyamakawa satyamakawa CreatorName Yamakawa, Satoshi
	NRID 1000020512049 1000020512049 researchmap permalink kanamoto kanamoto Scopus Author ID 7005012135 7005012135 CreatorName Kanamoto, Takashi
	NRID 1000000283747 1000000283747 researchmap permalink ken-nakata ken-nakata Scopus Author ID 7402151308 7402151308 CreatorName Nakata, Ken
	NRID 1000030448435 1000030448435 ORCID 0000-0002-5107-8209 0000-0002-5107-8209 researchmap permalink okadaseiji okadaseiji Scopus Author ID 35079139100 35079139100 CreatorName Okada, Seiji
	NRID 1000070612076 1000070612076 ORCID 0000-0002-2426-1024 0000-0002-2426-1024 researchmap permalink k-ebina k-ebina Scopus Author ID 8415453300 8415453300 CreatorName Ebina, Kosuke
Subject	Microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN)
	Osteoblast
	Osteoclast
	Osteocyte
	Postmenopausal osteoporosis
	RANKL
Description	Kurihara T., Shimamura M., Etani Y., et al. RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice. Bone 194, 117440 (2025); https://doi.org/10.1016/j.bone.2025.117440.
Abstract	Purpose: Estrogen deficiency following menopause increases receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, thereby promoting osteoclast differentiation, and enhances T cell-derived tumor necrosis factor-alpha (TNFα) production, which induces sclerostin expression in osteocytes, thereby inhibiting bone formation. This study aimed to develop a novel uncoupling therapeutic agent for osteoporosis. Methods: We developed microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), a modified RANKL peptide with N-terminal acetylation and C-terminal amidation lacking the osteoclast activating CD loop. Given the structural similarities of RANK and TNF receptor 1 (TNFR1), we hypothesized that MHP1-AcN could inhibit both the RANKL–RANK and TNFα–TNFR1 pathways to address the pathophysiology of osteoporosis, as evaluated in vitro and in vivo using an ovariectomized mouse model. Results: In ovariectomized mice, MHP1-AcN inhibited osteoclastogenesis, reduced osteocytic sclerostin expression, prevented bone loss, and improved the femoral cancellous and cortical bone microarchitecture. Unlike anti-RANKL antibody, MHP1-AcN considerably preserved bone formation by osteoblasts and enhanced bone strength, as evidenced by increases in energy absorption capacity. In vitro, MHP1-AcN bound to both RANK and TNFR1, suppressing osteoclast activity via the RANKL–RANK pathway and reducing sclerostin expression through the TNFα–TNFR1–nuclear factor-kappa B pathway. MHP1-AcN did not affect osteoblast proliferation and differentiation or RANKL expression. Conclusion: MHP1-AcN effectively inhibits osteoclastogenesis and sclerostin-mediated suppression of bone formation while considerably preserving osteoblast function. These findings suggest that MHP1-AcN, which targets dual pathways critical for bone homeostasis, is a promising uncoupling therapeutic agent for osteoporosis.
Publisher	Elsevier Inc.
Source Title	Bone
Volume (Issue)	194
Page	117440
Date of Issued	2025-05-01
Language	English
Handle URL	https://hdl.handle.net/11094/100972
PISSN	87563282
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.bone.2025.117440
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 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
DCTERMS.bibliographicCitation	Bone. 2025, 194, p. 117440
DC.title	RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice
DC.creator	Kurihara, Takuya
	Shimamura, Munehisa
	Etani, Yuki
	Noguchi, Takaaki
	Fukuda, Yuji
	Ochiai, Nagahiro
	Goshima, Atsushi
	Miura, Taihei
	Hirao, Makoto
	Sugimoto, Atsushi
	Ju, Nan
	Yamakawa, Satoshi
	Kanamoto, Takashi
	Nakata, Ken
	Okada, Seiji
	Ebina, Kosuke
DC.publisher	Elsevier Inc.
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-05-01
DC.identifier	https://doi.org/10.1016/j.bone.2025.117440
DC.subject	Microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN)
	Osteoblast
	Osteoclast
	Osteocyte
	Postmenopausal osteoporosis
	RANKL
DC.description	Kurihara T., Shimamura M., Etani Y., et al. RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice. Bone 194, 117440 (2025); https://doi.org/10.1016/j.bone.2025.117440.
DCTERMS.abstract	Purpose: Estrogen deficiency following menopause increases receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, thereby promoting osteoclast differentiation, and enhances T cell-derived tumor necrosis factor-alpha (TNFα) production, which induces sclerostin expression in osteocytes, thereby inhibiting bone formation. This study aimed to develop a novel uncoupling therapeutic agent for osteoporosis. Methods: We developed microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), a modified RANKL peptide with N-terminal acetylation and C-terminal amidation lacking the osteoclast activating CD loop. Given the structural similarities of RANK and TNF receptor 1 (TNFR1), we hypothesized that MHP1-AcN could inhibit both the RANKL–RANK and TNFα–TNFR1 pathways to address the pathophysiology of osteoporosis, as evaluated in vitro and in vivo using an ovariectomized mouse model. Results: In ovariectomized mice, MHP1-AcN inhibited osteoclastogenesis, reduced osteocytic sclerostin expression, prevented bone loss, and improved the femoral cancellous and cortical bone microarchitecture. Unlike anti-RANKL antibody, MHP1-AcN considerably preserved bone formation by osteoblasts and enhanced bone strength, as evidenced by increases in energy absorption capacity. In vitro, MHP1-AcN bound to both RANK and TNFR1, suppressing osteoclast activity via the RANKL–RANK pathway and reducing sclerostin expression through the TNFα–TNFR1–nuclear factor-kappa B pathway. MHP1-AcN did not affect osteoblast proliferation and differentiation or RANKL expression. Conclusion: MHP1-AcN effectively inhibits osteoclastogenesis and sclerostin-mediated suppression of bone formation while considerably preserving osteoblast function. These findings suggest that MHP1-AcN, which targets dual pathways critical for bone homeostasis, is a promising uncoupling therapeutic agent for osteoporosis.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	100972
citation_title	RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice
citation_author	Kurihara, Takuya
	Shimamura, Munehisa
	Etani, Yuki
	Noguchi, Takaaki
	Fukuda, Yuji
	Ochiai, Nagahiro
	Goshima, Atsushi
	Miura, Taihei
	Hirao, Makoto
	Sugimoto, Atsushi
	Ju, Nan
	Yamakawa, Satoshi
	Kanamoto, Takashi
	Nakata, Ken
	Okada, Seiji
	Ebina, Kosuke
citation_publisher	Elsevier Inc.
citation_language	English
citation_date	2025-05-01
citation_journal_title	Bone
citation_volume	194
citation_firstpage	117440
citation_doi	https://doi.org/10.1016/j.bone.2025.117440
citation_public_url	https://hdl.handle.net/11094/100972

RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice

Link to primary information

Item Information

Show details