Characterization of a Novel Col1a1G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations

Saitou, Hiroyuki; Ohata, Yasuhisa; Takeyari, Shinji; Nishizawa, Chiaki; Nakayama, Hirofumi; Fujiwara, Makoto; Kitabatake, Yasuji; Kubota, Takuo; Ozono, Keiichi

doi:https://doi.org/10.1007/s00223-024-01320-2

Characterization of a Novel Col1a1G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations

Saitou, Hiroyuki; Ohata, Yasuhisa; Takeyari, Shinji et al.

Calcified Tissue International, 2025, 116(13)

Number of Access:1,335（2025-07-22 20:43 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100318

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Title	Characterization of a Novel Col1a1G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations
Creator	NRID 1000000723909 1000000723909 CreatorName Saitou, Hiroyuki
	NRID 1000020805460 1000020805460 ORCID 0000-0001-6084-6620 0000-0001-6084-6620 researchmap permalink pedmed pedmed Scopus Author ID 25626528000 25626528000 CreatorName Ohata, Yasuhisa
	NRID 1000070774454 1000070774454 ORCID 0000-0002-3627-1932 0000-0002-3627-1932 researchmap permalink shinji_takeyari shinji_takeyari CreatorName Takeyari, Shinji
	ORCID 0009-0000-4799-1049 0009-0000-4799-1049 researchmap permalink u291314 u291314 CreatorName Nishizawa, Chiaki
	ORCID 0009-0009-5142-6822 0009-0009-5142-6822 researchmap permalink nkym1623 nkym1623 Scopus Author ID 57204722838 57204722838 CreatorName Nakayama, Hirofumi
	NRID 1000050625697 1000050625697 ORCID 0000-0002-6799-9774 0000-0002-6799-9774 researchmap permalink makofuji1977 makofuji1977 Scopus Author ID 57203794801 57203794801 CreatorName Fujiwara, Makoto
	NRID 1000080506494 1000080506494 ORCID 0000-0002-2907-9512 0000-0002-2907-9512 researchmap permalink kyasuji kyasuji Scopus Author ID 7003894272 7003894272 CreatorName Kitabatake, Yasuji
	NRID 1000040629135 1000040629135 ORCID 0000-0003-4483-4405 0000-0003-4483-4405 researchmap permalink k_b_t k_b_t Scopus Author ID 8236245700 8236245700 CreatorName Kubota, Takuo
	NRID 1000020270770 1000020270770 ORCID 0000-0002-6517-8825 0000-0002-6517-8825 researchmap permalink read0092357 read0092357 Scopus Author ID 55545335700 55545335700 CreatorName Ozono, Keiichi
Subject	Col1a1
	Glycine substitution
	Micro-CT analysis
	Mouse model
	Osteogenesis imperfecta
	Three-point bending test
Description	The version of record of this article, first published in Calcified Tissue International, is available online at Publisher’s website: https://doi.org/10.1007/s00223-024-01320-2.
Abstract	Osteogenesis imperfecta (OI) is an inheritable skeletal disorder characterized by bone fragility often caused by pathogenic variants in the COL1A1 gene. Current OI mouse models with a glycine substitution in Col1a1 exhibit excessive severity, thereby limiting long-term pathophysiological analysis and drug effect assessments. To address this limitation, we constructed a novel OI mouse model mimicking a patient with OI type III. This was achieved by introducing a G-to-A transversion at nucleotide position 2428 in the Col1a1 gene via CRISPR-Cas9 technology in C57BL/6 J mice. The resulting heterozygous variant mice (Col1a1G643S/+) displayed reduced body weight and pronounced skeletal abnormalities. Micro-CT analysis at 12 weeks revealed decreased vertebral bone parameters and altered cortical bone characteristics, indicative of bone fragility. Additionally, the abnormalities of the anisotropy, complexity, connectivity, and structure of trabecular bone were revealed. A three-point bending test confirmed the fragility, with reduced displacement and fracture energy in both sexes. Furthermore, we evaluated the effect of 4-phenylbutyric acid on the bone in Col1a1G643S/+ mice at 12 weeks, observing no significant effects, likely due to the absence of collagen retention in the ER in this model. Despite being a moderate OI model, Col1a1G643S/+ mice manifest a distinct and fragile bone phenotype, making them suitable for extended studies. This model offers a valuable platform for investigating long-term pathophysiological aspects of OI and assessing the efficacy of potential therapeutic interventions.
Publisher	Springer
Source Title	Calcified Tissue International
Volume (Issue)	116(13)
Date of Issued	2025-01-03
Language	English
Handle URL	https://hdl.handle.net/11094/100318
PISSN	0171967X
eISSN	14320827
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1007/s00223-024-01320-2
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
DCTERMS.bibliographicCitation	Calcified Tissue International. 2025, 116(13)
DC.title	Characterization of a Novel Col1a1G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations
DC.creator	Saitou, Hiroyuki
	Ohata, Yasuhisa
	Takeyari, Shinji
	Nishizawa, Chiaki
	Nakayama, Hirofumi
	Fujiwara, Makoto
	Kitabatake, Yasuji
	Kubota, Takuo
	Ozono, Keiichi
DC.publisher	Springer
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-01-03
DC.identifier	https://doi.org/10.1007/s00223-024-01320-2
DC.subject	Col1a1
	Glycine substitution
	Micro-CT analysis
	Mouse model
	Osteogenesis imperfecta
	Three-point bending test
DC.description	The version of record of this article, first published in Calcified Tissue International, is available online at Publisher’s website: https://doi.org/10.1007/s00223-024-01320-2.
DCTERMS.abstract	Osteogenesis imperfecta (OI) is an inheritable skeletal disorder characterized by bone fragility often caused by pathogenic variants in the COL1A1 gene. Current OI mouse models with a glycine substitution in Col1a1 exhibit excessive severity, thereby limiting long-term pathophysiological analysis and drug effect assessments. To address this limitation, we constructed a novel OI mouse model mimicking a patient with OI type III. This was achieved by introducing a G-to-A transversion at nucleotide position 2428 in the Col1a1 gene via CRISPR-Cas9 technology in C57BL/6 J mice. The resulting heterozygous variant mice (Col1a1G643S/+) displayed reduced body weight and pronounced skeletal abnormalities. Micro-CT analysis at 12 weeks revealed decreased vertebral bone parameters and altered cortical bone characteristics, indicative of bone fragility. Additionally, the abnormalities of the anisotropy, complexity, connectivity, and structure of trabecular bone were revealed. A three-point bending test confirmed the fragility, with reduced displacement and fracture energy in both sexes. Furthermore, we evaluated the effect of 4-phenylbutyric acid on the bone in Col1a1G643S/+ mice at 12 weeks, observing no significant effects, likely due to the absence of collagen retention in the ER in this model. Despite being a moderate OI model, Col1a1G643S/+ mice manifest a distinct and fragile bone phenotype, making them suitable for extended studies. This model offers a valuable platform for investigating long-term pathophysiological aspects of OI and assessing the efficacy of potential therapeutic interventions.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100318
citation_title	Characterization of a Novel Col1a1G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations
citation_author	Saitou, Hiroyuki
	Ohata, Yasuhisa
	Takeyari, Shinji
	Nishizawa, Chiaki
	Nakayama, Hirofumi
	Fujiwara, Makoto
	Kitabatake, Yasuji
	Kubota, Takuo
	Ozono, Keiichi
citation_publisher	Springer
citation_language	English
citation_date	2025-01-03
citation_journal_title	Calcified Tissue International
citation_volume	116
citation_issue	13
citation_doi	https://doi.org/10.1007/s00223-024-01320-2
citation_public_url	https://hdl.handle.net/11094/100318

Characterization of a Novel Col1a1G643S/+ Osteogenesis Imperfecta Mouse Model with Insights into Skeletal Phenotype, Fragility, and Therapeutic Evaluations

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