RSPOs facilitated HSC activation and promoted hepatic fibrogenesis

Yin, Xiaonan; Yi, Huixing; Wang, Linlin; Wu, Wanxin; Wu, Xiaojun; Yu, Linghua

doi:10.18632/oncotarget.11654

Cited by 23 publications

(18 citation statements)

References 26 publications

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“…These findings seem to be more compelling when we consider what we have learned from our in vivo studies where the anti-fibrotic activity of anti-RSPO3 OMP131R10 was closely related to the overexpression of RSPO3 in the fibrotic lesions. Unlike what was previously reported where RSPO expression was measured in a Western blotting, we could not detect significant elevation of RSPO1 or RSPO2 in CCl 4 livers by IHC [34]. The discrepancy could be due to different antibodies used and the sensitivity of different detection methods.…”

Section: Discussioncontrasting

confidence: 99%

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Zhang¹,

Haughey²,

Wang³

et al. 2020

PLoS ONE

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The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl 4 )-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis. PLOS ONEPLOS ONE | https://doi.org/10.

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Section: Discussioncontrasting

confidence: 99%

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Zhang¹,

Haughey²,

Wang³

et al. 2020

PLoS ONE

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“…Interestingly, a family of agonists for the canonical Wnt pathway, roof plate-specific spondins (RSPOs), increase hepatic stellate cell activation and induce liver fibrosis in mice through canonical signalling activation. 66 RSPOs were found to be elevated in human fibrotic liver and an inhibitor of the canonical pathway, DKK1, is able to prevent RSPO-Wnt induced liver fibrosis. 66 On the other hand, Wnt5a has been suggested to have profibrotic activities and is under the control of TGFβ in liver fibroblasts.…”

Section: Wnt Signalling In Cmdsmentioning

confidence: 98%

Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases

Ackers

Malgor

2017

Diabetes and Vascular Disease Research

120

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Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation.

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“…In contrast, β-catenin-dependent canonical Wnt activation is required to maintain quiescent state of HSCs in vitro [154]. Roof plate-specific spondin (RSPO) proteins, potent Wnt pathway agonists, suppressed HSC activation, which is impaired by DKK1 [155]. In activated rat HSCs, non-canonical Wnt pathway activation dominates and confers HSC survival, accompanied with Wnt5a over-expression [156].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,078

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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RSPOs facilitated HSC activation and promoted hepatic fibrogenesis

Cited by 23 publications

References 26 publications

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases

Hepatic stellate cells as key target in liver fibrosis

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