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Review
. 2022 Sep 2:13:954454.
doi: 10.3389/fphys.2022.954454. eCollection 2022.

The Wnt signaling cascade in the pathogenesis of osteoarthritis and related promising treatment strategies

Jinchao Cheng  1 , Min Li  1 , Ruijun Bai  2
Affiliations
Review

The Wnt signaling cascade in the pathogenesis of osteoarthritis and related promising treatment strategies

Jinchao Cheng et al. Front Physiol. .

Abstract

Osteoarthritis (OA) is the most prevalent joint disease, characterized by the degradation of articular cartilage, synovial inflammation, and changes in periarticular and subchondral bone. Recent studies have reported that Wnt signaling cascades play an important role in the development, growth, and homeostasis of joints. The Wnt signaling cascade should be tightly regulated to maintain the homeostasis of cartilage in either the over-activation or the suppression of Wnt/β-catenin, as this could lead to OA. This review summarizes the role and mechanism of canonical Wnt cascade and noncanonical Wnt cascade experiments in vivo and in vitro. The Wnt cascade is controlled by several agonists and antagonists in the extracellular medium and the cytoplasm. These antagonists and agonists serve as key molecules in drug intervention into the Wnt pathway and may provide potential approaches for the treatment of OA. However, the complexity of the Wnt signaling cascade and the pharmaceutical effects on its mechanism are still not fully understood, which forces us to conduct further research and develop efficient therapeutic approaches to treat OA.

Keywords: chondrocyte; osteoarthritis; therapy; wnt signaling; β-catenin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The canonical Wnt signaling pathway is dependent on the activation of intracellular molecule β-catenin. In the absence of Wnt-binding Fz receptors, β-catenin is isolated into a protein, phosphorylated, and subsequently degraded by the destruction complex. Upon binding to the Fzl receptors and LRP5/6 co-receptors, the Wnt/β-catenin signaling pathways is activated while the degradation complex of β-catenin is inhibited, allowing the newly synthesized β-catenin to accumulate in the cytoplasm and transfer to the nucleus. Nuclear β-catenin can replace the transcription corepressors in TCF transcription factors and promote the activation of gene transcription programs.
FIGURE 2
FIGURE 2
The non-canonical Wnt signaling cascade is activated without the involvement and activation of β-catenin. The Wnt protein binds to Fzl and other ligand receptors without the engagement of the LRP co-receptors. One of these cascades is triggered by the stimulation of the intracellular Ca2+ secondary to the production of the cytoplasmic PLC, subsequently activating the transcription factors in cell nucleus through the regulation of CaMKII; the other non-canonical Wnt signaling cascade relies on the increase of Rho following the activation of mitogen-activated kinases such as c-Jun N-terminal kinase (JNK), targeting the genes, and regulating cell proliferation and migration.
FIGURE 3
FIGURE 3
Complex role of Wnts in chondrocytes, synoviocytes, and mesenchymal stem cells. Low Wnt/β-catenin activity in chondrocytes promotes chondrocyte proliferation, chondrogenic differentiation, chondrocyte hypertrophy, and increased ECM synthesis, while high Wnt/β-catenin activity leads to chondrocyte apoptosis, hypertrophy, increased inflammation, and degradation of ECM in joints. Overexpression β-catenin contributes to the fibrocyte proliferation, pannus formation, and local inflammation in synoviocytes; moreover, it could also promote the proliferation and chondrogenic differentiation of MSCs in joints.
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