The WNT1G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV

TY - JOUR

T1 - The WNT1G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV

AU - Vollersen, Nele

AU - Zhao, Wenbo

AU - Rolvien, Tim

AU - Lange, Fabiola

AU - Schmidt, Felix Nikolai

AU - Sonntag, Stephan

AU - Shmerling, Doron

AU - von Kroge, Simon

AU - Stockhausen, Kilian Elia

AU - Sharaf, Ahmed

AU - Schweizer, Michaela

AU - Karsak, Meliha

AU - Busse, Björn

AU - Bockamp, Ernesto

AU - Semler, Oliver

AU - Amling, Michael

AU - Oheim, Ralf

AU - Schinke, Thorsten

AU - Yorgan, Timur Alexander

N1 - © 2021. The Author(s).

PY - 2021/11/10

Y1 - 2021/11/10

N2 - 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 Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/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.

AB - 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 Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/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.

U2 - 10.1038/s41413-021-00170-0

DO - 10.1038/s41413-021-00170-0

M3 - SCORING: Journal article

C2 - 34759273

VL - 9

SP - 48

JO - BONE RES

JF - BONE RES

SN - 2095-4700

IS - 1

ER -