המידע באדיבות מדיקונטקסט
Last Updated: 2001-07-10 16:57:15 EDT (Reuters Health)
By Will Boggs, MD
WESTPORT, CT (Reuters Health) – California researcher have found that c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, plays a critical role in metalloproteinase expression and joint destruction in inflammatory arthritis.
Overexpression of matrix metalloproteinases (MMP) causes rheumatoid joint destruction and MMP production might be controlled in part by increased activation of JNK, the authors explain in the July issue of The Journal of Clinical Investigation.
Dr. Gary S. Firestein, from the University of California, San Diego, School of Medicine, in La Jolla, California, and colleagues used SP600125, a novel selective JNK inhibitor, to investigate the role of JNK in a mouse model of arthritis.
SP600125 blocked IL-1-stimulated JNK activity in fibroblast-like synoviocytes by directly inhibiting JNK activity, the authors report. In addition, SP600125 completely suppressed collagenase mRNA accumulation and AP-1 binding, a key regulator of MMP production.
Systemic administration of SP600125 completely inhibited JNK activity in the joints of rats with adjuvant arthritis, the report indicates, resulting in modest decreases in joint swelling.
More importantly, the investigators report, SP600125 administration was accompanied by marked decreases in bone and cartilage damage in the affected joints of rats with adjuvant arthritis.
"These data indicate that the JNK pathway lies at a critical convergent point in the regulation of extracellular matrix regulation in arthritis," the authors conclude. "Hence, JNK inhibition is a potential therapeutic approach for prevention of matrix destruction."
"Understanding the molecular mechanisms of inflammation and destruction can identify therapeutic targets that can have an major impact on disease," Dr. Firestein told Reuters Health. "We are not that far away from traditional small molecule therapeutics (as opposed to biologics that are very expensive and are given parenterally), since lead compounds are already being generated."
"The hope is that JNK inhibitors would be effective at any stage of disease. In our model, we initiated therapy before the joint destruction occurred, which certainly suggests that early therapy would be effective," Dr. Firestein concluded.
J Clin Invest 2001;108:73-81.
-Westport Newsroom 203 319 2700
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