Biological activity of a genetically modified BMP-2 variant with inhibitory activity.
BACKGROUND
Alterations of the binding epitopes of bone morphogenetic protein-2 (BMP-2) lead to a modified interaction with the ectodomains of BMP receptors. In the present study the biological effect of a BMP-2 double mutant with antagonistic activity was evaluated in vivo.


METHODS
Equine-derived collagenous carriers were loaded with recombinant human BMP-2 (rhBMP-2) in a well-known dose to provide an osteoinductive stimulus. The study was performed in a split animal design: carriers only coupled with rhBMP-2 (control) were implanted into prepared cavities of lower limb muscle of rats, specimens coupled with rhBMP-2 as well as BMP-2 double mutant were placed into the opposite limb in the same way. After 28 days the carriers were explanted, measured radiographically and characterized histologically.


RESULTS
As expected, the BMP-2 loaded implants showed a typical heterotopic bone formation. The specimens coupled with both proteins showed a significant decreased bone formation in a dose dependent manner.


CONCLUSIONS
The antagonistic effect of a specific BMP-2 double mutant could be demonstrated in vivo. The dose dependent influence on heterotopic bone formation by preventing rhBMP-2 induced osteoinduction suggests a competitive receptor antagonism.
Klammert
Uwe
U
Department of Cranio-Maxillo-Facial Surgery, University of Würzburg, Pleicherwall 2, 97070 Würzburg, Germany. uweklammert@yahoo.com
Nickel
Joachim
J
Würzler
Kristian
K
Klingelhöffer
Christoph
C
Sebald
Walter
W
Kübler
Alexander C
AC
Reuther
Tobias
T
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000494:pharmacology*; D052004:Bone Morphogenetic Protein Receptors / Q000037:antagonists & inhibitors*; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D000939:Epitopes / Q000494:pharmacology; D006614:Hindlimb; D018482:Muscle, Skeletal; D009154:Mutation; D009999:Ossification, Heterotopic / Q000517:prevention & control; D010012:Osteogenesis / Q000187:drug effects*; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004343:Drug Implants; D000939:Epitopes; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D052004:Bone Morphogenetic Protein Receptors