Water‐soluble C60 fullerene prevents degeneration of articular cartilage in osteoarthritis via down‐regulation of chondrocyte catabolic activity and inhibition of cartilage degeneration during disease development

Abstract

Objective. Studies have shown the roles of oxidative stress in the pathogenesis of osteoarthritis (OA) and induction of chondrocyte senescence during OA progression. The aim of this study was to examine the potential of a strong free-radical scavenger, watersoluble fullerene (C60), as a protective agent against catabolic stress-induced degeneration of articular cartilage in OA, both in vitro and in vivo.Methods. In the presence or absence of C60 (100 M), human chondrocytes were incubated with interleukin-1␤ (10 ng/ml) or H 2 O 2 (100 M), and chondrocyte activity was analyzed. An animal model of OA was produced in rabbits by resection of the medial meniscus and medial collateral ligament. Rabbits were divided into 5 subgroups: sham operation or treatment with C60 at 0.1 M, 1 M, 10 M, or 40 M. The left knee joint was injected intraarticularly with watersoluble C60 (2 ml), while, as a control, the right knee joint received 50% polyethylene glycol (2 ml), once weekly for 4 weeks or 8 weeks. Knee bone and cartilage tissue were prepared for histologic analysis. In addition, in the OA rabbit model, the effect of C60 (10 M) on degeneration of articular cartilage was compared with that of sodium hyaluronate (HA) (5 mg/ml).Results. C60 (100 M) inhibited the catabolic stress-induced production of matrix-degrading enzymes (matrix metalloproteinases 1, 3, and 13), downregulation of matrix production, and apoptosis and premature senescence in human chondrocytes in vitro.In rabbits with OA, treatment with water-soluble C60 significantly reduced articular cartilage degeneration, whereas control knee joints showed progression of cartilage degeneration with time. This inhibitory effect was dose dependent, and was superior to that of HA. Combined treatment with C60 and HA yielded a significant reduction in cartilage degeneration compared with either treatment alone. Conclusion.The results indicate that C60 fullerene is a potential therapeutic agent for the protection of articular cartilage against progression of OA.During the development of osteoarthritis (OA), mechanical and chemical stresses on articular cartilage change the stable cellular activities of chondrocytes and stimulate the production of growth factors and matrix proteins as well as inflammation mediators (1-4). It is well known that catabolic-stressed chondrocytes produce excess amounts of reactive oxygen species (ROS) (superoxide, nitric oxide, hydrogen peroxide, and peroxynitrite) as well as proinflammatory cytokines and chemokines (4-9).Studies have provided ample confirmation of the generation of ROS and the depletion of cellular antioxidants in degenerated articular cartilage (8-10). Numerous reports have indicated that the degeneration of articular cartilage is partially mediated by oxygenderived free radicals (8-12). Kurz et al reported that the extent of mechanical stress on articular cartilage is sufficient to stimulate an excess production of ROS from chondrocytes, leading to depolymerization of hyaluronic acid and chondrocyte death (11,12). Similarly, Gree...

Water-soluble fullerene (C60) inhibits the osteoclast differentiation and bone destruction in arthritis

“…21,22 We have already demonstrated that water-soluble C60 fullerene, a strong free-radical scavenger, can function as a protective agent against catabolic stress-induced degeneration of articular cartilage in a model of osteoarthritis in vitro and in vivo. 23 Water-soluble C60 significantly reduced articular cartilage degeneration in the osteoarthritis rabbit model. These findings suggest that C60 has the potential to protect against oxygen free radical-induced pathological features in a variety of diseases.…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Mn salen derivatives were investigated as well (88). Along with metal-based SOD mimics, some nonmetallic and, thus far less-efficient compounds, such as nitroxides (140) and fullerenes (181,349), also have been explored. Further, covalently bound porphyrins and nitroxides were studied (160).…”

“…A carboxyfullerene protected the liver against carbon tetrachloride intoxication in rats (129). In an osteoarthritis model, a carboxylated C 60 prevented catabolic-stress-induced production of matrix metalloproteinases 1, 3, and 13, downregulation of matrix production, apoptosis, and premature senescence of human chondrocytes (treated with interleukin-1b) in vitro, and degeneration of articular cartilage in vivo, in rabbit knees (349). By using EPR measurements, Yin et al demonstrated the ROS (singlet oxygen, superoxide, and hydroxyl radical)-scavenging abilities of three water-soluble fullerenes, Gd-fullerenol, fullerenol, and carboxyfullerene (with two malonyl groups).…”

The Nicotinamide Adenine Dinucleotide (NAD)-Dependent Deacetylase Sirtuin-1 Regulates Chondrocyte Energy Metabolism through the Modulation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) in Osteoarthritis(OA)

“…Several reports indicate that sirtuins may have two important roles -"regulation of cellular metabolism" and "response to cellular stresses (stress tolerance)", which are closely involved in the pathogenesis and pathology of a variety of diseases including stress-induced degenerative diseases such as OA [11][12][13]. Various cellular stresses such as mechanical stress, oxidative stress, inflammation and aging have been recognized as major risk factors for OA, and all sources of stress could affect the regulation of chondrocyte metabolism [5][6][7][8][14][15][16][17]. Altered chondrocyte metabolism and changes in their responses to OA-related stresses are implicated in the creation of an imbalance between catabolic and anabolic reactions, leading to osteoarthritic degeneration of articular cartilage [5,8,17].…”