Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Osteoarthritis (OA) is a prevalent joint disorder with a significant unmet need for disease-modifying osteoarthritis drugs (DMOADS).
• Krüppel-like factor 4 (KLF4) is a key transcription factor involved in maintaining joint tissue health and regeneration.

Purpose of the Study:

• To identify small molecules that activate KLF4 expression.
• To investigate the therapeutic potential and underlying mechanisms of KLF4-activating compounds for OA treatment.

Main Methods:

• High-throughput screening (HTS) of 11,948 clinical-stage compounds using a KLF4 reporter cell line.
• In vitro validation in chondrocytes, meniscal cells, and mesenchymal stem cells.
• In vivo assessment of mocetinostat efficacy and pain behavior in OA mouse models.
• Global gene expression and proteomic analyses to elucidate molecular pathways.

Main Results:

• Mocetinostat, a selective histone deacetylase (HDAC) inhibitor, was identified as a potent KLF4 activator.
• Mocetinostat upregulated cartilage-associated genes and downregulated hypertrophic, inflammatory, and catabolic genes in various joint cells.
• In vivo administration of mocetinostat reduced OA severity and improved pain behaviors in mice.
• Therapeutic effects were linked to the upregulation of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α).

Conclusions:

• Mocetinostat demonstrates significant therapeutic and protective effects against osteoarthritis.
• Its ability to modulate KLF4 and PGC-1α pathways positions it as a promising candidate for a novel disease-modifying osteoarthritis drug (DMOAD).