Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function |
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Authors: | Email author" target="_blank">Kazuo?YudohEmail author Nguyen?van Trieu Hiroshi?Nakamura Kayo?Hongo-Masuko Tomohiro?Kato Kusuki?Nishioka |
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Institution: | (1) Department of Bioregulation, Institute of Medical Science, St. Marianna University, Kawasaki City, Japan |
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Abstract: | Oxidative stress leads to increased risk for osteoarthritis (OA) but the precise mechanism remains unclear. We undertook this
study to clarify the impact of oxidative stress on the progression of OA from the viewpoint of oxygen free radical induced
genomic instability, including telomere instability and resulting replicative senescence and dysfunction in human chondrocytes.
Human chondrocytes and articular cartilage explants were isolated from knee joints of patients undergoing arthroplastic knee
surgery for OA. Oxidative damage and antioxidative capacity in OA cartilage were investigated in donor-matched pairs of intact
and degenerated regions of tissue isolated from the same cartilage explants. The results were histologically confirmed by
immunohistochemistry for nitrotyrosine, which is considered to be a maker of oxidative damage. Under treatment with reactive
oxygen species (ROS; 0.1 μmol/l H2O2) or an antioxidative agent (ascorbic acid: 100.0 μmol/l), cellular replicative potential, telomere instability and production
of glycosaminoglycan (GAG) were assessed in cultured chondrocytes. In tissue cultures of articular cartilage explants, the
presence of oxidative damage, chondrocyte telomere length and loss of GAG to the medium were analyzed in the presence or absence
of ROS or ascorbic acid. Lower antioxidative capacity and stronger staining of nitrotyrosine were observed in the degenerating
regions of OA cartilages as compared with the intact regions from same explants. Immunostaining for nitrotyrosine correlated
with the severity of histological changes to OA cartilage, suggesting a correlation between oxidative damage and articular
cartilage degeneration. During continuous culture of chondrocytes, telomere length, replicative capacity and GAG production
were decreased by treatment with ROS. In contrast, treatment with an antioxidative agent resulted in a tendency to elongate
telomere length and replicative lifespan in cultured chondrocytes. In tissue cultures of cartilage explants, nitrotyrosine
staining, chondrocyte telomere length and GAG remaining in the cartilage tissue were lower in ROS-treated cartilages than
in control groups, whereas the antioxidative agent treated group exhibited a tendency to maintain the chondrocyte telomere
length and proteoglycan remaining in the cartilage explants, suggesting that oxidative stress induces chondrocyte telomere
instability and catabolic changes in cartilage matrix structure and composition. Our findings clearly show that the presence
of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage,
suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development
of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing
oxidative damage in articular cartilage. |
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