A tumor necrosis factor-alpha antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingivalis infection in mice.
BACKGROUND
A tumor-necrosis factor-alpha (TNF-alpha) antagonist, the WP9QY peptide, was designed based on the crystal structure of the TNF-beta/TNF-receptor complex in order to overcome the disadvantages of macromolecules such as antibodies or soluble receptors by reducing the molecular size of TNF-alpha antagonists. It efficiently antagonizes the effect of TNF-alpha binding to the TNF receptor (I).


OBJECTIVE
The aim of the present study was to assess the effects of the WP9QY peptide on inflammatory bone resorption and osteoclast formation in the periodontal pathogen-infection model.


METHODS
Live Porphyromonas gingivalis ATCC 33277 was injected once daily for 6 days into the subcutaneous tissue overlying the calvariae in mice. At the same time, the WP9QY peptide (1 mg/kg, 2 mg/kg or 4 mg/kg per day) was administrated via osmotic minipumps for 7 days. Histological observations and the radiological assessments of the calvariae as well as bone mineral density measurements were performed.


RESULTS
The WP9QY peptide significantly prevented the P. gingivalis-induced reduction in the bone mineral density at the calvariae. The histomorphometric assessments revealed the inhibitiory effects of the WP9QY peptide on the P. gingivalis-induced increase in the number of the inflammatory cells and in the area of sagittal suture at the calvariae. Furthermore, there was also an inhibitory effect on the P. gingivalis-induced increase in the number of osteoclasts per unit bone surface at the calvariae.


CONCLUSIONS
These results suggest that the strategy for the design to reduce the molecular size of the TNF-alpha antagonists would be beneficial for the treatment of local inflammatory bone loss induced by periodontal-pathogen infection.
Suzuki
Yoshifumi
Y
Section of Periodontology, Graduate School, Tokyo Medical and Dental University, Japan. kazu.hpha@tmd.ac.jp
Aoki
Kazuhiro
K
Saito
Hiroaki
H
Umeda
Makoto
M
Nitta
Hiroshi
H
Baron
Roland
R
Ohya
Keiichi
K
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D015519:Bone Density; D001862:Bone Resorption / Q000209:etiology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000378:metabolism; D015195:Drug Design; D015918:Infusion Pumps, Implantable; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010000:Osteitis / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D010010:Osteoclasts / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D016966:Porphyromonas gingivalis / Q000472:pathogenicity; D011485:Protein Binding; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D012886:Skull; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C501648:WP9QY peptide