Mice carrying a ubiquitous R235W mutation of Wnt1 display a bone-specific phenotype

TY - JOUR

T1 - Mice carrying a ubiquitous R235W mutation of Wnt1 display a bone-specific phenotype

AU - Yorgan, Timur

AU - Rolvien, Tim

AU - Stürznickel, Julian

AU - Vollersen, Nele

AU - Lange, Fabiola

AU - Zhao, Wenbo

AU - Baranowsky, Anke

AU - Rosenthal, Lana

AU - Hermans-Borgmeyer, Irm

AU - Sharaf, Ahmed

AU - Karsak, Meliha

AU - David, Jean-Pierre

AU - Oheim, Ralf

AU - Amling, Michael

AU - Schinke, Thorsten

N1 - © 2020 American Society for Bone and Mineral Research.

PY - 2020/9

Y1 - 2020/9

N2 - Since a key function of Wnt1 in brain development was established early on through the generation of non-viable Wnt1-deficient mice, it was initially surprising that WNT1 mutations were found to cause either early-onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OI-XV). The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mouse models with bone-specific inactivation or overexpression, but mice carrying disease-causing Wnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygous WNT1 mutation (p.R235W), we introduced this mutation into the murine Wnt1 gene to address the question of whether this would cause a skeletal phenotype. We observed that Wnt1 +/R235W and Wnt1 R235W/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious nonskeletal phenotypes. At 12 weeks of age, the homozygous presence of the Wnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate compared with wild-type littermates. At 52 weeks of age, we also observed a moderate bone mass reduction in heterozygous Wnt1 +/R235W mice, thereby underscoring their value as a model of WNT1-dependent EOOP. Importantly, when we treated wild-type and Wnt1 +/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together with an increased cortical thickness in the mutant mice. Our data demonstrate the pathogenicity of the WNT1-R235W mutation, confirm that controlling skeletal integrity is the primary physiological function of Wnt1, and suggest that osteoanabolic treatment with teriparatide should be applicable for individuals with WNT1-dependent EOOP. © 2020 American Society for Bone and Mineral Research.

AB - Since a key function of Wnt1 in brain development was established early on through the generation of non-viable Wnt1-deficient mice, it was initially surprising that WNT1 mutations were found to cause either early-onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OI-XV). The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mouse models with bone-specific inactivation or overexpression, but mice carrying disease-causing Wnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygous WNT1 mutation (p.R235W), we introduced this mutation into the murine Wnt1 gene to address the question of whether this would cause a skeletal phenotype. We observed that Wnt1 +/R235W and Wnt1 R235W/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious nonskeletal phenotypes. At 12 weeks of age, the homozygous presence of the Wnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate compared with wild-type littermates. At 52 weeks of age, we also observed a moderate bone mass reduction in heterozygous Wnt1 +/R235W mice, thereby underscoring their value as a model of WNT1-dependent EOOP. Importantly, when we treated wild-type and Wnt1 +/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together with an increased cortical thickness in the mutant mice. Our data demonstrate the pathogenicity of the WNT1-R235W mutation, confirm that controlling skeletal integrity is the primary physiological function of Wnt1, and suggest that osteoanabolic treatment with teriparatide should be applicable for individuals with WNT1-dependent EOOP. © 2020 American Society for Bone and Mineral Research.

U2 - 10.1002/jbmr.4043

DO - 10.1002/jbmr.4043

M3 - SCORING: Journal article

C2 - 32369212

VL - 35

SP - 1726

EP - 1737

JO - J BONE MINER RES

JF - J BONE MINER RES

SN - 0884-0431

IS - 9

ER -