Enhancing effects of a prostaglandin EP4 receptor agonist on recombinant human bone morphogenetic protein-2 mediated spine fusion in a rabbit model.
METHODS
An experimental animal study aimed at achieving posterolateral intertransverse process fusion with rhBMP-2 in combination with the local delivery of an EP4 receptor agonist.


OBJECTIVE
To determine whether an EP4 receptor agonist (EP4A) can reduce the amount of BMP required to achieve posterolateral spinal fusion in rabbits.


BACKGROUND
In the clinic, BMP retaining implants are used for spinal fusion and the treatment of pseudarthrosis after long bone fracture. However, the requirement of high doses of BMP-2 for bone formation in humans makes the implants expensive and limits their use in the clinic. Previous studies in our laboratory using a new delivery system involving a synthetic polymer/beta-TCP powder composite had shown it was possible to reduce the total BMP-2 amount to 30 microg per fusion in a rabbit model. To further reduce the dose of BMP required for a successful fusion, we explored the use of a chemical compound to enhance the bone-inducing action of BMP-2.


METHODS
In order to prepare 1 implant to bridge the unilateral L5 and L6 transverse processes, 300 mg of polymer gel (PLA-DX-PEG block copolymer), 300 mg of beta-TCP powder, rhBMP-2 (7.5, 3.75, or 0 microg), with or without EP4A (45 microg) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, 2 implants were placed on both sides (1 per side) by surgery in order to bridge the transverse processes of adult New Zealand white rabbits (n = 48). The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology.


RESULTS
All of 8 rabbits that received 7.5 microg of BMP-2 and EP4A consistently showed fusion by significant amount of new bone formation. However, solid fusion was seen in only 3 of 8 rabbits that received 7.5 microg of BMP-2 without the EP4 receptor agonist.


CONCLUSIONS
Local administration of an EP4 receptor agonist enhanced the bone-inducing activity of BMP-2 in a rabbit posterolateral lumbar spinal fusion model and as a result, the dose of BMP-2 required for this outcome was reduced by 50% compared with our previous report. The coadministration of this compound via a local delivery system may help to reduce the costs of spine fusion with use of BMP-2 in the clinic.
Namikawa
Takashi
T
Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan. namikawa@msic.med.osaka-cu.ac.jp
Terai
Hidetomi
H
Hoshino
Masatoshi
M
Kato
Minori
M
Toyoda
Hiromitsu
H
Yano
Koichi
K
Nakamura
Hiroaki
H
Takaoka
Kunio
K
D000818:Animals; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D004357:Drug Synergism; D006537:Heptanoates / Q000494:pharmacology; D023421:Models, Animal; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011994:Recombinant Proteins / Q000494:pharmacology*; D013123:Spinal Fusion / Q000379:methods; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006537:Heptanoates; C487764:ONO4819; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2