OBJECTIVE: The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor alpha (TNFalpha) recognition loop on TNF receptor I, and it prevents interactions of TNFalpha with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen-induced arthritis (CIA) in mice with those of anti-TNFalpha monoclonal antibody. METHODS: CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti-TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed. RESULTS: WP9QY treatment inhibited CIA-induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti-TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA-induced bone destruction at the knee joints to the same extent as did anti-TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA-induced systemic bone loss by WP9QY was more apparent than that by anti-TNF antibody. CONCLUSION: The TNFalpha antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.
OBJECTIVE: The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor alpha (TNFalpha) recognition loop on TNF receptor I, and it prevents interactions of TNFalpha with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen-induced arthritis (CIA) in mice with those of anti-TNFalpha monoclonal antibody. METHODS: CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti-TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed. RESULTS: WP9QY treatment inhibited CIA-induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti-TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA-induced bone destruction at the knee joints to the same extent as did anti-TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA-induced systemic bone loss by WP9QY was more apparent than that by anti-TNF antibody. CONCLUSION: The TNFalpha antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.
Authors: Leo R Fitzpatrick; Cecelia Green; Elizabeth E Frauenhoffer; Kevin J French; Yan Zhuang; Lynn W Maines; John J Upson; Emmanuel Paul; Henry Donahue; Timothy J Mosher; Charles D Smith Journal: Inflammopharmacology Date: 2010-10-11 Impact factor: 4.473
Authors: K Mihara; C Almansa; R L Smeets; E E M G Loomans; J Dulos; P M F Vink; M Rooseboom; H Kreutzer; F Cavalcanti; A M Boots; R L Nelissen Journal: Br J Pharmacol Date: 2008-02-25 Impact factor: 8.739