HDAC6 regulates NF-κB signalling to control chondrocyte IL-1-induced MMP and inflammatory gene expression

Area of Science:

• Molecular Biology
• Immunology
• Rheumatology

Background:

• Arthritis involves pro-inflammatory signaling and matrix metalloproteinase (MMP) expression, causing cartilage damage and joint dysfunction.
• Histone deacetylase inhibitors (HDACi) show potential in preclinical arthritis models by suppressing MMPs and inflammation.

Purpose of the Study:

• To identify specific histone deacetylases (HDACs) responsible for chondro-protective effects in arthritis.
• To elucidate the role of HDAC6 in pro-inflammatory signaling and NF-κB pathway activation in chondrocytes.

Main Methods:

• Conducted an RNA interference (RNAi) screen targeting HDAC1-11 in chondrocytes.
• Investigated the effect of HDAC6 depletion on interleukin-1 (IL-1) induced MMP and pro-inflammatory cytokine expression.
• Analyzed the impact of HDAC6 on inhibitor of κB (IκB) levels, NF-κB subunit nuclear translocation, and NF-κB reporter activity.

Main Results:

• HDAC6 was essential for IL-1 induced MMP and pro-inflammatory interleukin expression in chondrocytes.
• Depletion of HDAC6 led to increased IκB, inhibited NF-κB nuclear translocation, and reduced NF-κB reporter activation.
• Pharmacological inhibition of HDAC6 decreased MMP expression and cartilage collagen release.

Conclusions:

• HDAC6 plays a critical role in mediating pro-inflammatory signaling and metalloproteinase gene expression in arthritis.
• HDAC6 is implicated in the NF-κB signaling pathway, regulating key inflammatory mediators.
• Targeting HDAC6 represents a promising therapeutic strategy for protecting cartilage in arthritis.