Class I histone deacetylases and their inhibitors as targets to modulate cellular senescence in osteoarthritis

Area of Science:

• Biochemistry
• Cell Biology
• Gerontology

Background:

• Cellular senescence, characterized by senescent cell (SC) accumulation, contributes to age-related musculoskeletal conditions like osteoarthritis (OA).
• Targeting SCs is a promising therapeutic strategy for age-related diseases.

Purpose of the Study:

• To investigate the role of Class I histone deacetylases (HDACs) in chondrocyte senescence.
• To evaluate the senolytic potential of the HDAC inhibitor mocetinostat in osteoarthritis.

Main Methods:

• Analysis of Class I HDAC expression during senescence in immortalized human chondrocytes (TC28a2).
• Knockdown experiments to determine the function of HDAC1 and HDAC2 in chondrocyte viability and inflammation.
• Treatment of senescent and non-senescent chondrocytes with mocetinostat to assess its selective toxicity and effects on gene expression.

Main Results:

• Class I HDACs, except HDAC1, were downregulated in senescent chondrocytes.
• HDAC1 is vital for chondrocyte survival, while HDAC2 influences inflammation via NF-κB signaling.
• Mocetinostat selectively induced apoptosis in senescent chondrocytes, sparing non-senescent cells.
• Mocetinostat modulated inflammation- and chondrogenesis-related gene expression.

Conclusions:

• Class I HDACs play a critical role in chondrocyte survival and extracellular matrix gene regulation.
• Mocetinostat demonstrates senolytic efficacy against senescent chondrocytes, suggesting its potential as a therapeutic agent for OA and other aging-related musculoskeletal disorders.