Inhibition of Leukotriene A4 Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis.

Abstract

Objective: Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB₄) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase-activating protein, Leukotriene A₄ hydrolase (LTA₄H) and its downstream product LTB₄. The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB₄ pathway in OA disease progression.

Design: Both clinical human cartilage samples (n = 7) and mice experimental OA models (n = 6) were used. The levels of LTA₄H and leukotriene B4 receptor 1 were first examined using immunostaining in human OA/non-OA cartilage and mice experimental OA models. We also determined whether the LTA₄H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes.

Results: We found that both LTA₄H and LTB₄ receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA₄H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA₄H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan (ACAN), collagen 2A1 (COL2A1), and SRY-Box transcription factor 9 (SOX9).

Conclusions: Our results indicate that the LTA₄H pathway is a crucial regulator of OA pathogenesis and suggest that LTA₄H could be a therapeutic target in combat OA.