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

Abstract

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 HNEtrapping 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.

Differential Effects of Superoxide Dismutase Mimetics after Mechanical Overload of Articular Cartilage

“…Thus, our data support the use of SOD acutely; however, increases in protection by the aqueous mimetics are lost at higher doses possibly suggesting a more nuanced redox environment where increasing superoxide removal becomes detrimental, possibly as a result of too much hydrogen peroxide product at high doses of GC4403 and T2E. Alternatively, in the repeated overload scenario there is a strong coherence between protection of mitochondrial function with BuOE, our prior results demonstrating the benefits of NAC and MitoQ in this setting [ 19 , 22 ], and existing literature showing critical interactions between lipid peroxidation and the glutathione system [ 33 , 34 ]. These studies imply that oxidative damage to mitochondrial lipids resulting from mechanical injury or other stresses feeds forward into general oxidative stress responses mediated by the intracellular thiol systems.…”

“…These studies imply that oxidative damage to mitochondrial lipids resulting from mechanical injury or other stresses feeds forward into general oxidative stress responses mediated by the intracellular thiol systems. Throughout PTOA pathogenesis as inflammation ebbs and flows, tissue begins to degrade, and local mechanics become further disrupted, chronic indications of lipid peroxidation and the involvement of intracellular thiols are noted at many stages [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 33 , 34 ]. This suggests that future attempts to improve the chronic redox environment within chondrocytes in response to mechanical overload will need to account for the state of the tissue, from healthy to arthritic, and the nature of the mechanical overload itself.…”

In‐vivo three‐dimensional knee kinematics during daily activities in dogs

“…Given the morphological similarities, the dog is a well‐established animal model for investigating diseases and evaluating new treatments for the human knee . The anterior cruciate ligament (ACL) deficient canine model, also known as the Pond–Nuki Model, reliably causes abnormal kinematics, and is thus utilized to investigate the pathogenesis of mechanically‐induced osteoarthritis . The canine knee has been used as a preclinical animal model for ACL reconstruction methods, posterolateral injuries, and meniscal surgery .…”

“…1 The anterior cruciate ligament (ACL) deficient canine model, also known as the Pond-Nuki Model, reliably causes abnormal kinematics, and is thus utilized to investigate the pathogenesis of mechanically-induced osteoarthritis. [2][3][4][5] The canine knee has been used as a preclinical animal model for ACL reconstruction methods, 6,7 posterolateral injuries, 8 and meniscal surgery. 9 Additionally, one of the leading causes of pelvic limb lameness in dogs is naturally occurring ACL degeneration, which is estimated to cost US pet owners $1.3 billion annually.…”

The mitochondrial inhibitor oligomycin induces an inflammatory response in the rat knee joint

“…In synovial tissue from patients with inflammatory arthritis, 4-HNE is associated with a greater frequency of mtDNA mutations, which are associated with a higher presence of macroscopic features of inflammation, increased expression of pro-inflammatory cytokines, and a greater vascularization and infiltration of CD68+ and CD3+ cells [11, 12, 50]. Altogether, these data could support the idea that the inflammatory response induced in the rat knee joint by exposure to oligomycin is mediated by ROS production.…”