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N-Acetylcysteine Inhibits Post-Impact Chondrocyte Death in Osteochondral Explants
James A. Martin, PhD1; Daniel McCabe, BS1; Morgan Walter, BS1; Joseph A. Buckwalter, MS, MD1; Todd O. McKinley, MD1
1 Orthopaedic Cell and Molecular Biology Laboratory, Department of Orthopaedics and Rehabilitation, The University of Iowa, 1182 ML, Iowa City, IA 52242. E-mail address for J.A. Martin: james-martin@uiowa.edu
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant 1 P50 AR055533). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the Orthopaedic Cell and Molecular Biology Laboratory, Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, Iowa

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2009 Aug 01;91(8):1890-1897. doi: 10.2106/JBJS.H.00545
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Background: Chondrocyte death has been linked to injury-induced oxidative damage, suggesting that antioxidants could substantially improve viability. However, since reactive oxygen species play roles in normal physiology, there are concerns that antioxidants may have deleterious side effects. To address these issues, we studied the effects of N-acetylcysteine, a potent free radical scavenger, on chondrocyte viability and cartilage proteoglycan content in an in vitro cartilage injury model. We hypothesized that treatment with N-acetylcysteine soon after an impact injury would have significant chondrocyte-sparing effects and would prevent injury-induced proteoglycan losses.

Methods: Bovine osteochondral explants were subjected to a single impact load with use of a drop-tower device. Chondrocyte viability was measured at multiple time points post-impact with use of fluorescent probes and confocal microscopy. Forty-eight hours after impact, the effects on viability of immediate post-impact treatment with N-acetylcysteine were compared with the effects of the caspase inhibitor N-CBZ-Val-Ala-Asp(O-Me) fluoromethyl ketone and those of the cell-membrane-stabilizing surfactant poloxamer 188. The effect of N-acetylcysteine on proteoglycan content was determined at seven and fourteen days post-impact.

Results: Chondrocyte viability declined sharply within an hour and reached a steady state within six to twelve hours after impact. Immediate treatment with N-acetylcysteine doubled the number of viable chondrocytes assayed forty-eight hours after impact, and this effect was significantly greater than that of N-CBZ-Val-Ala-Asp(O-Me) fluoromethyl ketone. Even when N-acetylcysteine treatment was delayed for up to four hours after injury, it still had significant positive effects on cell viability at forty-eight hours. Moreover, N-acetylcysteine treatment significantly improved proteoglycan content at the impact sites at both seven and fourteen days after injury.

Conclusions: Treatment with N-acetylcysteine soon after a blunt impact injury can reduce chondrocyte death and proteoglycan loss measured seven to fourteen days after injury.

Clinical Relevance: These findings suggest that antioxidant protection in the early aftermath of joint injury may help to reduce chondrocyte death and stabilize the articular cartilage.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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