Universität zu Köln

Vollersen, Nele, Zhao, Wenbo ORCID: 0000-0002-3418-9433, Rolvien, Tim, Lange, Fabiola, Schmidt, Felix Nikolai, Sonntag, Stephan, Shmerling, Doron, von Kroge, Simon, Stockhausen, Kilian Elia, Sharaf, Ahmed, Schweizer, Michaela, Karsak, Meliha, Busse, Bjoern, Bockamp, Ernesto, Semler, Oliver, Amling, Michael, Oheim, Ralf, Schinke, Thorsten and Yorgan, Timur Alexander (2021). The WNT1(G177C) mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV. Bone Res., 9 (1). LONDON: SPRINGERNATURE. ISSN 2095-6231

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Abstract

The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1(G177C/G177C) mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1(G177C/G177C) mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vollersen, Nele UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Wenbo UNSPECIFIED orcid.org/0000-0002-3418-9433 UNSPECIFIED Rolvien, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Lange, Fabiola UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Felix Nikolai UNSPECIFIED UNSPECIFIED UNSPECIFIED Sonntag, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Shmerling, Doron UNSPECIFIED UNSPECIFIED UNSPECIFIED von Kroge, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Stockhausen, Kilian Elia UNSPECIFIED UNSPECIFIED UNSPECIFIED Sharaf, Ahmed UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweizer, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Karsak, Meliha UNSPECIFIED UNSPECIFIED UNSPECIFIED Busse, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Bockamp, Ernesto UNSPECIFIED UNSPECIFIED UNSPECIFIED Semler, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Amling, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Oheim, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Schinke, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Yorgan, Timur Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-592368
DOI:	10.1038/s41413-021-00170-0
Journal or Publication Title:	Bone Res.
Volume:	9
Number:	1
Date:	2021
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2095-6231
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRABECULAR ARCHITECTURE; INT-1 PROTOONCOGENE; WNT1 MUTATIONS; BONE; GENE; OSTEOPOROSIS; DENSITY; OSTEOCLASTOGENESIS; SCLEROSTIN; EXPRESSION Multiple languages Cell & Tissue Engineering Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59236