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.