New Evidence Implicating 4‐Hydroxynonenal in the Pathogenesis of Osteoarthritis In Vivo

Objective To demonstrate the involvement of 4-hydroxynonenal (HNE), a very reactive aldehyde derived from lipid peroxidation, in the pathogenesis of osteoarthritis (OA) in vivo. Methods In the first experimental protocol, OA was induced by anterior cruciate ligament transection (ACLT) of the right knees of crossbred dogs (n = 6 per group). The animals were treated with placebo or HNE-trapping carnosine (5 or 20 mg/kg/day) orally for 8 weeks. Another group of dogs was treated for 4 weeks with 20 mg/kg/day of carnosine starting 4 weeks after surgery. Sham-operated dogs served as controls. In the second experimental protocol, a pathophysiologic dose of HNE (80 nmoles/ml) or vehicle was injected weekly into the right knee joints of crossbred dogs (n = 6 per group) for 8 weeks. Articular cartilage was subjected to macroscopic, histomorphologic, and immunohistochemical analyses. Cartilage-degrading enzymes and oxidative stress–related products were assessed in synovial fluid and cartilage explants. Markers of inflammation were evaluated in synovium and synovial fluid. Results In dogs that had undergone ACLT, carnosine treatment reduced the severity and histopathology score of OA cartilage lesions and also decreased HNE–protein adducts, pentosidine, nitrosylated proteins, cartilage-degrading enzymes, and markers of inflammation. Intraarticular injection of HNE induced cartilage lesions, as assessed by macroscopic and microscopic criteria. Cartilage-degrading enzymes and markers of inflammation increased in HNE-treated dogs. Conclusion This is the first in vivo study to demonstrate the pathophysiologic role of HNE in OA. That carnosine abolishes HNE production and a number of factors known to be involved in OA pathogenesis renders it a clinically valuable agent in prevention of the disease.