Wnt/β-catenin Signaling Pathway: Reactivation of the "Developmental Program" in Fibrosis

Introduction: Why Does a Pathway Important for Development Promote Fibrosis?

The Wnt/β-catenin signaling pathway is essential for body axis formation and organ development during the embryonic period, and in adults, it is mainly involved in stem cell maintenance and tissue repair. However, it has become clear that when this "developmental program" is ectopically reactivated by chronic injury or inflammation in adult organs that are normally quiescent, it causes pathological fibrosis (Nature Reviews Molecular Cell Biology). Persistent activation of Wnt/β-catenin signaling is commonly observed in fibrosis of diverse organs such as the lungs, kidneys, liver, and skin, and is attracting attention as a therapeutic target.

1. Canonical Wnt Signaling: Nuclear Translocation of β-catenin

While there are multiple Wnt signaling pathways, the one most deeply related to fibrosis is the "Canonical Pathway (β-catenin-dependent pathway)."

Signal "OFF" State: Degradation of β-catenin

In the absence of Wnt ligands, cytoplasmic β-catenin is constantly degraded by the "Destruction complex."

• Axin: Scaffold protein.
• APC (Adenomatous Polyposis Coli): Tumor suppressor gene product.
• CK1 (Casein Kinase 1), GSK3 (Glycogen Synthase Kinase 3): Enzymes that phosphorylate β-catenin.

Phosphorylated β-catenin is ubiquitinated and degraded by the proteasome.

Signal "ON" State: Accumulation and Nuclear Translocation of β-catenin

When Wnt ligands (Wnt1, Wnt3a, Wnt7b, etc.) bind to receptor complexes on the cell membrane, the following changes occur:

1. Receptor Activation: Frizzled receptor (FZD) and its co-receptor LRP5/6 form a complex.
2. Inhibition of Destruction Complex: Via Dishevelled (Dvl) protein, the destruction complex becomes dysfunctional.
3. Accumulation of β-catenin: β-catenin, no longer degraded, accumulates in the cytoplasm.
4. Translocation to Nucleus: β-catenin moves into the nucleus and binds to transcription factors TCF/LEF.
5. Target Gene Expression: Transcription of Wnt target genes is activated.

Expression of Fibrosis-Related Genes

When the Wnt/β-catenin pathway is activated, fibrosis-related genes such as the following are induced:

• Snail1, Twist: Promote EMT (Epithelial-Mesenchymal Transition).
• Fibronectin, MMP-7: Deposition and reorganization of ECM.
• PAI-1: Inhibition of ECM degradation.
• FSP1, α-SMA: Myofibroblast markers.

2. Organ-Specific Roles of Wnt Signaling

Renal Fibrosis

• In healthy adult kidneys, Wnt/β-catenin signaling is mostly silent.
• Reactivated by renal injury (diabetic nephropathy, chronic nephritis, etc.), promoting tubulointerstitial fibrosis (J Am Soc Nephrol).
• Wnt3a/β-catenin in macrophages induces M2 polarization, accelerating fibrosis.

Pulmonary Fibrosis (IPF)

• In lung tissue of Idiopathic Pulmonary Fibrosis (IPF) patients, increased nuclear β-catenin and high expression of Wnt target genes (Cyclin D1, MMP-7) are confirmed.
• Wnt signaling in lung epithelial cells and fibroblasts promotes EMT and collagen synthesis.

Liver Fibrosis

• Wnt/β-catenin signaling is involved in the activation of Hepatic Stellate Cells (HSCs).
• HSCs proliferate and survive due to Wnt signal activation, enhancing collagen production.

3. Crosstalk with TGF-β

The Wnt/β-catenin pathway and the TGF-β pathway mutually enhance each other (Frontiers in Physiology).

• Wnt Induction by TGF-β: TGF-β stimulation increases expression of Wnt ligands.
• TGF-β Enhancement by Wnt: Wnt activation increases fibroblast responsiveness to TGF-β.
• Common Target Genes: EMT-related transcription factors (Snail, Twist, etc.) are common targets of both pathways.

Due to this synergistic effect, single pathway inhibition may have limited efficacy, necessitating simultaneous targeting of multiple pathways.

4. Wnt/β-catenin Signaling as a Therapeutic Target

Development of Wnt Inhibitors

• ICG-001: Inhibits the interaction between β-catenin and transcriptional coactivator CBP. Anti-fibrotic effects reported in renal and pulmonary fibrosis models (J Am Soc Nephrol).
• PRI-724: An improved version of ICG-001. Suppressed HSC activation and promoted inflammation resolution in liver fibrosis models.
• DKK1 (Dickkopf-1): Endogenous Wnt signaling inhibitor. Competitively inhibits binding to LRP5/6.
• Small Molecule Inhibitors: GSK3β inhibitors, etc., are in research stages.

Challenges and Prospects

Since Wnt signaling is also essential for tissue repair and stem cell maintenance, systemic inhibition carries risks of side effects (delayed wound healing, stem cell dysfunction). Organ-specific delivery systems and selective inhibition of specific downstream targets (e.g., β-catenin/CBP interaction) are required.

Conclusion

The Wnt/β-catenin signaling pathway is a beneficial mechanism working at the "right place and right time" during development, but in adult chronic diseases, it is reactivated at the "wrong place and wrong time," driving fibrosis. Appropriate control of this pathway, alongside the TGF-β pathway, is key to next-generation anti-fibrotic therapies. Our fibrosis models serve as a platform to evaluate the efficacy of therapeutics targeting the Wnt pathway, from the molecular level to the tissue level.

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References

1. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149(6):1192-1205.
2. Akhmetshina A, et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun. 2012;3:735.
3. He W, et al. Wnt/β-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009;20(4):765-776.