The presence of molecular markers of in vivo lipid peroxidation in osteoarthritic cartilage: A pathogenic role in osteoarthritis

Abstract

Objective. To investigate the role of oxidative functions in human osteoarthritic (OA) chondrocytes and to investigate the presence of in vivo molecular markers of lipoxidation in OA cartilage.Methods. An in vitro model of cartilage collagen degradation was used. Lipid peroxidation activity and overall oxidative function in OA chondrocytes were monitored by cis-parinaric acid and dichlorofluorescein assays, respectively. In vivo molecular markers of lipoxidation in normal and OA cartilage were studied using immunohistochemistry to detect the presence of malondialdehyde and hydroxynonenal adducts.Results. Human OA chondrocytes showed a robust amount of 3 H-proline-labeled collagen degradation upon stimulation with lipopolysaccharide and calcium ionophore A21387, as compared with that in untreated OA chondrocytes. Primary OA chondrocytes showed both spontaneous and inducible levels of lipid peroxidation activity. However, lipid peroxidation activity was already maximally elevated in more than 50% of the OA chondrocyte samples. Overall, spontaneous and inducible oxidative activities were observed in all OA samples. Immunohistochemical analysis of control OA tissue sections that were not treated with monoclonal antibody showed little immunoreactivity. OA cartilage sections treated with monoclonal antibodies showed specific immunoreactivity on the cartilage surface, at sites of OA lesions, at the pericellular matrix, and at intra-and intercellular matrices. Normal cartilage sections showed faint surface reactivity.Conclusion. Our observations suggest that human OA chondrocytes demonstrate spontaneous and inducible cell-associated lipoxidative and nonlipoxidative activity. Lipoxidative activity appears to be enhanced in OA chondrocytes. The presence of molecular markers of in vivo lipid peroxidation was demonstrated in OA cartilage, suggesting its role in the pathogenesis of the disease.Osteoarthritis (OA) is the most common form of joint disease that affects humans. The incidence of OA increases during every decade of life, and by the age of 65 years, almost one-third of the population has OA of the knee joints. The economic burden attributed to the joint pain and disability of OA amounts to billions of dollars each year (1). As the population demographic in the US changes to a predominantly older generation, the increasing prevalence of OA will be a major public health problem.There is currently no treatment available that will prevent or cure OA. Pharmacologic and nonpharmacologic agents used for OA provide only symptomatic relief of pain. The lack of specific therapy for this disease is perhaps due to our limited understanding of its pathogenesis. Understanding the molecular mechanisms involved in the development of OA will help us to develop ways to prevent or reverse the degenerative process of the disease.Current concepts of the pathogenic mechanisms of OA suggest that there is a shift in the homeostatic balance between the destruction and synthesis of bone and cartilage, with a net progressive destruction of t...

Susceptibility of knee osteoarthritis patients to develop cardiovascular disease - a clinical study

“…11 In particular, malondialdehyde (MDA), a toxic 12 Shah et al also showed that chondrocyte derived lipid peroxidation mediates collagen degradation. 1 In the present study, erythrocyte MDA levels were significantly high (p<0.05 & p<0.001) in study group subjects, which clarify the role of lipid peroxidation in knee OA progression and development of CVD risk. Oxidation of lipids is well controlled by antioxidant enzymes including plasma paraoxonase, an enzyme found in association with HDL contributing it to anti-atherogenic and antioxidant capability by hydrolyzing specific oxidized phospholipids and cholesterol linoleate hydroperoxides, and by neutralizing hydrogen peroxide.…”

“…The incidence of OA increases during every decade of life, and by the age of 65 years, most of the elderly has OA of knee joints. 1 Its prominent feature is the progressive destruction of articular cartilage which results in impaired joint motion, severe pain, structural and functional failure of synovial joints. 2 Consequently, the patients become physically inactive.…”

Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways

“…The hypothesis that this imbalance in signaling may result from the excessive levels of ROS that have been observed in OA cartilage (14,17,18) was supported by the findings that induction of oxidative stress in normal chondrocytes with tBHP reproduced the changes seen in OA cells, whereas treatment of OA cells with anti-oxidants improved the balance of Akt to ERK phosphorylation and improved the anabolic response of the cells to IGF-I.…”

“…Oxidative Stress Inhibits IGF-I-mediated IRS-1-Akt Signaling but Activates MEK-ERK-We hypothesized that increased levels of endogenous ROS due to oxidative stress, previously shown to be present in OA cells (11,14,17,18), might act to inhibit IGF-I signaling. To test this, we induced oxidative stress in normal human chondrocytes by incubating cultures for 30 min with 250 M tBHP.…”

Attenuation of adjuvant-induced arthritis by dietary sesamol via modulation of inflammatory mediators, extracellular matrix degrading enzymes and antioxidant status

“…Lipid peroxides could behave as secondary toxic trigger causing further damage by modulating membrane fluidity, permeability and transport, enhancing the risk of CVDs in arthritic patients [35]. Protein modification leads to malfunctioning of a variety of regulatory, structural and functional proteins like cell receptors, signal transducers and enzymes [36].…”