Dataset Information

Excessive Activation of TLR4/NF-?B Interactively Suppresses the Canonical Wnt/?-catenin Pathway and Induces SANFH in SD Rats.

ABSTRACT: Nuclear factor-kappa B (NF-?B) interactively affects the Wnt/?-catenin pathway and is closely related to different diseases. However, such crosstalk effect in steroid-associated necrosis of femoral head (SANFH) has not been fully explored and evaluated. In this study, early-stage SANFH was induced by two doses of lipopolysaccharide (LPS, 2?mg/kg/day) and three doses of methylprednisolone (MPS, 40?mg/kg/day). LPS and pyrrolidine dithiocarbamate (PDTC) were administered to activate the TLR4/NF-?B pathway and selectively block the activation of NF-?B, respectively. Results showed that PDTC treatment significantly reduced NF-?B expression, diminished inflammation, and effectively decreased bone resorption processes (osteoclastogenesis, adipogenesis, and apoptosis), which were evidently reinforced after osteonecrosis induction. Moreover, PDTC remarkably increased the interfered Wnt/?-catenin pathway and elevated bone formation processes (osteogenesis and angiogenesis). Ultimately, PDTC treatment effectively reduced the incidence of SANFH. Therefore, the excessive activation of TLR4/NF-?B may interactively suppress the Wnt/?-catenin pathway and induce SANFH. Hence, we propose NF-?B-targeted treatment as a novel therapeutic strategy for SANFH.

SUBMITTER: Pei J

PROVIDER: S-EPMC5607349 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Excessive Activation of TLR4/NF-κB Interactively Suppresses the Canonical Wnt/β-catenin Pathway and Induces SANFH in SD Rats.

Pei Junpeng J Fan Lihong L Nan Kai K Li Jia J Shi Zhibin Z Dang Xiaoqian X Wang Kunzheng K

Scientific reports 20170920 1

Nuclear factor-kappa B (NF-κB) interactively affects the Wnt/β-catenin pathway and is closely related to different diseases. However, such crosstalk effect in steroid-associated necrosis of femoral head (SANFH) has not been fully explored and evaluated. In this study, early-stage SANFH was induced by two doses of lipopolysaccharide (LPS, 2 mg/kg/day) and three doses of methylprednisolone (MPS, 40 mg/kg/day). LPS and pyrrolidine dithiocarbamate (PDTC) were administered to activate the TLR4/NF-κB ...[more]

PMID: 28931847

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Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Dataset Information

Excessive Activation of TLR4/NF-?B Interactively Suppresses the Canonical Wnt/?-catenin Pathway and Induces SANFH in SD Rats.

Publications

Excessive Activation of TLR4/NF-κB Interactively Suppresses the Canonical Wnt/β-catenin Pathway and Induces SANFH in SD Rats.

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