Antitumor necrotic factor agent promotes BMP-2-induced ectopic bone formation.
Etanercept (ETN), which is a recombinant human soluble tumor necrosis factor (TNF) receptor that inhibits TNF activity, is effective in the treatment of rheumatoid arthritis. We investigated the effect of ETN on recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced ectopic bone formation in vivo. A block copolymer composed of poly-D,L-lactic acid with random insertion of p-dioxanone and polyethylene glycol (PLA-DX-PEG polymer) was used as the delivery system. Polymer discs (6 mm, 30 mg) containing 5 microg rhBMP-2 were implanted into the left dorsal muscle pouch of mice (n = 50). In the systemic administration groups (n = 5 per group), ETN was subcutaneously injected (25 mg/human = 12.5 microg/mouse) twice per week in a dose-dependent manner (placebo, 12.5 x 10(-3), 12.5 x 10(-1), 12.5, 125 microg), whereas a single dose of ETN (placebo, 12.5 x 10(-3), 12.5 x 10(-1), 12.5, 125 microg) was embedded in each rhBMP-2 polymer disc in the local administration groups (n = 5 per group). Three weeks after implantation, the mice were killed and the implants were analyzed. Implants in the optimally dosed groups had increased radiodensity, which was consistent with a significant increase in bone mineral content of the ossicles. Bone histomorphology revealed a significant increase in bone volume/total volume, number of osteoblasts, osteoblast surface/bone surface, and a significant decrease in the number of osteoclasts, osteoclast surface/bone surface in the optimal dosed systemic and locally administered groups. These data suggest that the optimal dose of ETN, administered either systemically or locally, enhanced the bone-inducing capacity of BMP with no apparent adverse systemic effects.
Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
Yoshitaka
Y
Eguchi
Shigeyuki
S
Wakitani
Yuuki
Y
Imai
Yoshifumi
Y
Naka
Yuusuke
Y
Hashimoto
Hiroaki
H
Nakamura
Kunio
K
Takaoka
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004357:Drug Synergism; D000068800:Etanercept; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology*; D013977:Tibia / Q000033:anatomy & histology / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004343:Drug Implants; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C499469:recombinant human bone morphogenetic protein-2; D000068800:Etanercept