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.
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, water-soluble 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 microM), human chondrocytes were incubated with interleukin-1beta (10 ng/ml) or H2O2 (100 microM), 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 microM, 1 microM, 10 microM, or 40 microM. The left knee joint was injected intraarticularly with water-soluble 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 microM) on degeneration of articular cartilage was compared with that of sodium hyaluronate (HA) (5 mg/ml).


RESULTS
C60 (100 microM) inhibited the catabolic stress-induced production of matrix-degrading enzymes (matrix metalloproteinases 1, 3, and 13), down-regulation 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.


CONCLUSIONS
The results indicate that C60 fullerene is a potential therapeutic agent for the protection of articular cartilage against progression of OA.
Yudoh
Kazuo
K
St. Marianna University School of Medicine, Kawasaki, Japan. yudo@marianna-u.ac.jp
Shishido
Kiyoshi
K
Murayama
Hideki
H
Yano
Mitsunobu
M
Matsubayashi
Kenji
K
Takada
Hiroya
H
Nakamura
Hiroshi
H
Masuko
Kayo
K
Kato
Tomohiro
T
Nishioka
Kusuki
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D016166:Free Radical Scavengers / Q000494:pharmacology*; D037741:Fullerenes / Q000494:pharmacology*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000628:therapy*; D018384:Oxidative Stress / Q000187:drug effects; D011817:Rabbits
D000276:Adjuvants, Immunologic; D016166:Free Radical Scavengers; D037741:Fullerenes; D006820:Hyaluronic Acid; C069837:fullerene C60