Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand

Luther, Julia; Yorgan, Timur Alexander; Rolvien, Tim; Ulsamer, Lorenz; Koehne, Till; Liao, Na; Keller, Daniela; Vollersen, Nele; Teufel, Stefan; Neven, Mona; Peters, Stephanie; Schweizer, Michaela; Trumpp, Andreas; Rosigkeit, Sebastian; Bockamp, Ernesto; Mundlos, Stefan; Kornak, Uwe; Oheim, Ralf; Amling, Michael; Schinke, Thorsten; David, Jean Pierre

doi:10.1126/scitranslmed.aau7137

Cited by 70 publications

(67 citation statements)

References 58 publications

(73 reference statements)

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“…Together with the reduced osteogenic differentiation of ST2 cells transfected with a mutant Wnt1 expression plasmid, these findings clearly demonstrate the pathogenicity of the WNT1 ‐R235W mutation. Consistent with previously published data showing that Wnt1 deletion or overexpression in osteoblast lineage cells primarily affects bone formation,(23–25) we found that 12‐week‐old Wnt1 R235W/R235W mice displayed a reduced trabecular bone formation rate, which was assessed in spine sections. Of note, this difference was observed before a significant reduction of the trabecular bone volume was identified in the respective vertebral bodies.…”

Section: Discussionsupporting

confidence: 92%

Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype

Yorgan

Rolvien

Stürznickel

et al. 2020

Journal of Bone and Mineral Research

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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 Wnt1R235W/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.

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Section: Discussionsupporting

confidence: 92%

Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype

Yorgan

Rolvien

Stürznickel

et al. 2020

Journal of Bone and Mineral Research

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“…This pathway has been shown to contribute to cervical cancer pathology in various stages, including tumor initiation, progression, invasion, and therapeutic resistance [39,40]. As a member of the Wnt family, Wnt1 has been shown to involve in tumor progression, adaptive immune resistance and bone remodeling [41][42][43]. In our study, we identified Wnt1 as a key downstream effector of NEK2 in cervical cancer.…”

Section: Discussionmentioning

confidence: 61%

Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Zeng

Shi

et al. 2020

J Exp Clin Cancer Res

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Background NEK2, a serine/threonine kinase involved in mitosis, has been found to function in chromosome instability, tumor progression and metastasis, but its role in cervical cancer radioresistance remains unknown. Methods We detected the protein levels of NEK2 in cervical carcinoma tissues and paired paracarcinoma tissues by immunohistochemistry. The roles of NEK2 in oncogenesis were examined using cell growth and colony formation assays, EdU assay, apoptosis assay as well as in vivo mouse model. γ-H2AX and Rad51 foci formation, neutral comet assay and clonogenic cell survival assay were applied to determine the radiosensitivity of cervical cancer cells. RNA-seq was performed to identify the downstream effector of NEK2. The gene expression levels were measured by Real-time PCR. Results We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer tissues. Furthermore, we provided evidence that depletion of NEK2 impairs oncogenesis and enhances radiosensitivity in cervical cancer. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Conclusions Our results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.

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“…Loss of Wnt5a specifically in osteoclasts leads to reduced bone mass due to decreased bone formation, whereas deletion of its receptor Ror2 in OCs leads to increased bone mass, suggesting that Wnt5a activates both osteoblasts and osteoclasts, with a predominant effect on osteoblast function [22,35]. Mutations in Wnt1 have been shown to be responsible for osteoporosis and osteogenesis imperfecta, and transgenic overexpression of Wnt1 has been shown to markedly increase bone mass in mice [4,36]. In this study we found deregulation of Wnt5a as well as Wnt1 accompanying the increased osteoblast activity in miR-146a deficient mice.…”

Section: Discussionmentioning

confidence: 99%