A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti-tumor necrosis factor monoclonal antibody in murine collagen-induced 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.


CONCLUSIONS
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.
Saito
Hiroaki
H
Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kojima
Takefumi
T
Takahashi
Mariko
M
Horne
William C
WC
Baron
Roland
R
Amagasa
Teruo
T
Ohya
Keiichi
K
Aoki
Kazuhiro
K
D000043:Abstracting and Indexing; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb; D007596:Joints / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D010456:Peptides, Cyclic; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C501648:WP9QY peptide