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

Yorgan, Timur Alexander; Rolvien, Tim; Stürznickel, Julian; Vollersen, Nele; Lange, Fabiola; Baranowsky, Anke; Hermans‐Borgmeyer, Irm; David, Jean‐Pierre; Oheim, Ralf; Amling, Michael; Schinke, Thorsten

doi:10.1016/j.bonr.2020.100645

Cited by 1 publication

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“…Recently, the frizzled class receptor 10 has been suggested as a potential receptor for Wnt1 32 . Human mutations in the WNT1 gene lead to early‐onset osteoporosis or osteogenesis imperfecta, while various mouse models with Wnt1 mutations or osteoblast‐specific deficiency display bone loss and spontaneous fractures 30,31,33 . Our recent findings demonstrated that targeted Wnt1 induction specifically in osteoblasts enhances bone formation during fracture healing in healthy and osteoporotic conditions 34 .…”

Section: Introductionmentioning

confidence: 79%

“…32 Human mutations in the WNT1 gene lead to early-onset osteoporosis or osteogenesis imperfecta, while various mouse models with Wnt1 mutations or osteoblast-specific deficiency display bone loss and spontaneous fractures. 30,31,33 Our recent findings demonstrated that targeted Wnt1 induction specifically in osteoblasts enhances bone formation during fracture healing in healthy and osteoporotic conditions. 34 Furthermore, a recent study demonstrated Wnt1 expression upregulation in response to mechanical loading in osteocytes.…”

Section: Introductionmentioning

confidence: 96%

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Mechanical induction of osteoanabolic Wnt1 promotes osteoblast differentiation via Plat

Ahmad,

Haffner‐Luntzer,

Schoppa

et al. 2024

The FASEB Journal

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Physical activity‐induced mechanical stimuli play a crucial role in preserving bone mass and structure by promoting bone formation. While the Wnt pathway is pivotal for mediating the osteoblast response to loading, the exact mechanisms are not fully understood. Here, we found that mechanical stimulation induces osteoblastic Wnt1 expression, resulting in an upregulation of key osteogenic marker genes, including Runx2 and Sp7, while Wnt1 knockdown using siRNA prevented these effects. RNAseq analysis identified Plat as a major target through which Wnt1 exerts its osteogenic influence. This was corroborated by Plat depletion using siRNA, confirming its positive role in osteogenic differentiation. Moreover, we demonstrated that mechanical stimulation enhances Plat expression, which, in turn leads to increased expression of osteogenic markers like Runx2 and Sp7. Notably, Plat depletion by siRNA prevented this effect. We have established that Wnt1 regulates Plat expression by activating β‐Catenin. Silencing Wnt1 impairs mechanically induced β‐Catenin activation, subsequently reducing Plat expression. Furthermore, our findings showed that Wnt1 is essential for osteoblasts to respond to mechanical stimulation and induce Runx2 and Sp7 expression, in part through the Wnt1/β‐Catenin/Plat signaling pathway. Additionally, we observed significantly reduced Wnt1 and Plat expression in bones from ovariectomy (OVX)‐induced and age‐related osteoporotic mouse models compared with non‐OVX and young mice, respectively. Overall, our data suggested that Wnt1 and Plat play significant roles in mechanically induced osteogenesis. Their decreased expression in bones from OVX and aged mice highlights their potential involvement in post‐menopausal and age‐related osteoporosis, respectively.

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Section: Introductionmentioning

confidence: 79%