The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV
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,...
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Nature Publishing Group
2021
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oai:doaj.org-article:dec15195222f43c6a21a6c77c8ffa7fd2021-11-14T12:09:01ZThe WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV10.1038/s41413-021-00170-02095-6231https://doaj.org/article/dec15195222f43c6a21a6c77c8ffa7fd2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41413-021-00170-0https://doaj.org/toc/2095-6231Abstract 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.Nele VollersenWenbo ZhaoTim RolvienFabiola LangeFelix Nikolai SchmidtStephan SonntagDoron ShmerlingSimon von KrogeKilian Elia StockhausenAhmed SharafMichaela SchweizerMeliha KarsakBjörn BusseErnesto BockampOliver SemlerMichael AmlingRalf OheimThorsten SchinkeTimur Alexander YorganNature Publishing GrouparticleBiology (General)QH301-705.5PhysiologyQP1-981ENBone Research, Vol 9, Iss 1, Pp 1-13 (2021) |
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Biology (General) QH301-705.5 Physiology QP1-981 |
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Biology (General) QH301-705.5 Physiology QP1-981 Nele Vollersen Wenbo Zhao Tim Rolvien Fabiola Lange Felix Nikolai Schmidt Stephan Sonntag Doron Shmerling Simon von Kroge Kilian Elia Stockhausen Ahmed Sharaf Michaela Schweizer Meliha Karsak Björn Busse Ernesto Bockamp Oliver Semler Michael Amling Ralf Oheim Thorsten Schinke Timur Alexander Yorgan The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV |
| description |
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. |
| format |
article |
| author |
Nele Vollersen Wenbo Zhao Tim Rolvien Fabiola Lange Felix Nikolai Schmidt Stephan Sonntag Doron Shmerling Simon von Kroge Kilian Elia Stockhausen Ahmed Sharaf Michaela Schweizer Meliha Karsak Björn Busse Ernesto Bockamp Oliver Semler Michael Amling Ralf Oheim Thorsten Schinke Timur Alexander Yorgan |
| author_facet |
Nele Vollersen Wenbo Zhao Tim Rolvien Fabiola Lange Felix Nikolai Schmidt Stephan Sonntag Doron Shmerling Simon von Kroge Kilian Elia Stockhausen Ahmed Sharaf Michaela Schweizer Meliha Karsak Björn Busse Ernesto Bockamp Oliver Semler Michael Amling Ralf Oheim Thorsten Schinke Timur Alexander Yorgan |
| author_sort |
Nele Vollersen |
| title |
The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV |
| title_short |
The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV |
| title_full |
The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV |
| title_fullStr |
The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV |
| title_full_unstemmed |
The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV |
| title_sort |
wnt1 g177c mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type xv |
| publisher |
Nature Publishing Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/dec15195222f43c6a21a6c77c8ffa7fd |
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