Ketorolac tromethamine represses senescence in aging articular chondrocytes

Area of Science:

• Biomedical Science
• Cell Biology
• Pharmacology

Background:

• Osteoarthritis (OA) is characterized by cartilage degradation and cellular senescence.
• Interleukin-1β (IL-1β) is a key mediator in OA pathogenesis, promoting chondrocyte senescence.
• Cellular senescence contributes to the progression of OA.

Purpose of the Study:

• To investigate the therapeutic potential of ketorolac tromethamine in treating OA.
• To examine the effects of ketorolac tromethamine on IL-1β-induced cellular senescence in chondrocytes.
• To elucidate the role of cyclooxygenase-2 (COX-2) in ketorolac tromethamine's senolytic activity.

Main Methods:

• Human articular chondrocytes (HC-A) were challenged with IL-1β.
• Cellular senescence markers such as SA-β-Gal activity, G0/G1 phase arrest, MMP-3, MMP-13, p21, and p53 were assessed.
• Effects of varying concentrations of ketorolac tromethamine were evaluated.
• COX-2 expression and prostaglandin E2 (PGE2) levels were measured.
• COX-2 overexpression was used to investigate its role in ketorolac tromethamine's mechanism.

Main Results:

• IL-1β challenge induced cellular senescence in HC-A cells, evidenced by increased SA-β-Gal activity, G0/G1 arrest, elevated MMPs, and upregulated p21 and p53.
• Ketorolac tromethamine (25 and 50 mg/mL) significantly reversed these senescence markers.
• Ketorolac tromethamine inhibited IL-1β-induced COX-2 upregulation and PGE2 release.
• Overexpression of COX-2 abolished the inhibitory effects of ketorolac tromethamine on SA-β-Gal activity and p21/p53 upregulation.

Conclusions:

• Ketorolac tromethamine effectively represses cellular senescence in aging articular chondrocytes.
• The mechanism involves the inhibition of COX-2 signaling pathway.
• Ketorolac tromethamine shows promise as a therapeutic agent for osteoarthritis by targeting cellular senescence.