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

Abstract

Cellular senescence plays a significant role in age-related conditions like osteoarthritis (OA) and intervertebral disc degeneration, in part due to the accumulation of senescent cells (SCs) in musculoskeletal tissues. Identifying novel therapeutics that can clear SCs is crucial for improving musculoskeletal health in the elderly. The present study aimed to elucidate the changes in Class I histone deacetylases (HDACs) and their role during senescence. All Class I HDACs except HDAC1 were downregulated during senescence in the human TC28a2 immortalized human chondrocyte cell line. Knockdown experiments showed that HDAC1 is essential for maintaining the viability of both non-senescent cells (NSCs) and SCs, while HDAC2 plays a key role in modulating inflammation in part by targeting the NF-κB signaling pathway. Mocetinostat, an HDAC inhibitor, selectively kills senescent TC28a2 cells and primary human knee chondrocytes via apoptosis while not affecting the viability of NSCs. Mocetinostat also affected both inflammation-associated and chondrogenesis-associated genes. Overall, our findings demonstrate a key role of Class I HDACs in regulating chondrocyte survival and ECM gene expression. Mocetinostat holds promise as a senolytic therapeutic for OA and potentially other aging-related musculoskeletal disorders.