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-Mediated Activation of Human Chondrocytes1




*
Division of Rheumatology, Scripps Clinic, La Jolla, CA 92037; and
Division of Arthritis Research, The Scripps Research Institute, La Jolla, CA 92037
Glucosamine represents one of the most commonly used drugs to treat
osteoarthritis. However, mechanisms of its antiarthritic activities are
still poorly understood. The present study identifies a novel mechanism
of glucosamine-mediated anti-inflammatory activity. It is shown
that both glucosamine and N-acetylglucosamine inhibit
IL-1
- and TNF-
-induced NO production in normal human articular
chondrocytes. The effect of the sugars on NO production is specific,
since several other monosaccharides, including glucose, glucuronic
acid, and N-acetylmannosamine, do not express this
activity. Furthermore, N-acetylglucosamine polymers,
including the dimer and the trimer, also do not affect NO production.
The observed suppression of IL-1
-induced NO production is associated
with inhibition of inducible NO synthase mRNA and protein expression.
In addition, N-acetylglucosamine also suppresses the
production of IL-1
-induced cyclooxygenase-2 and IL-6. The
constitutively expressed cyclooxygenase-1, however, was not affected by
the sugar. N-acetylglucosamine-mediated inhibition of
the IL-1
response of human chondrocytes was not associated with the
decreased inhibition of the mitogen-activated protein kinases c-Jun
N-terminal kinase, extracellular signal-related kinase, and p38, nor
with activation of the transcription factor NF-
B. In conclusion,
these results demonstrate that N-acetylglucosamine
expresses a unique range of activities and identifies a novel mechanism
for the inhibition of inflammatory processes.
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