A complex interaction between Wnt signaling and TNF-α in nucleus pulposus cells

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Intervertebral disc (IVD) degeneration is linked to increased tumor necrosis factor-alpha (TNF-α).
• Wnt-β-catenin (Wnt) signaling activation suppresses nucleus pulposus (NP) cell proliferation and induces senescence, suggesting a role in IVD degeneration.
• The interplay between TNF-α and Wnt signaling in NP cells remains unclear.

Purpose of the Study:

• To investigate the interaction between Wnt signaling and TNF-α in regulating NP cells.
• To elucidate the role of this crosstalk in the pathogenesis of IVD degeneration.

Main Methods:

• Cultured rat NP cells and evaluated Wnt signaling and TNF-α expression and promoter activity.
• Utilized Wnt signaling inhibitors (Dickkopf isoforms, Sclerostin) and activators (BIO).
• Assessed the impact of TNF-α on Wnt signaling and vice versa, including using β-catenin small interfering RNA.

Main Results:

• TNF-α stimulation upregulated Wnt signaling expression and promoter activity in NP cells.
• Wnt signaling activation (using BIO) increased TNF-α expression and promoter activity.
• Inhibition of Wnt signaling with DKK-3, DKK-4, or SOST blocked TNF-α activation, while DKK-1 and DKK-2 had no effect.

Conclusions:

• Demonstrated a positive-feedback loop between Wnt signaling and TNF-α in NP cells.
• Wnt signaling activation upregulates TNF-α expression, potentially causing NP cell degeneration.
• Targeting this Wnt/TNF-α pathway may offer a therapeutic strategy against IVD degeneration.