title: Inhibition of endogenous antagonists with an engineered BMP-2 variant increases BMP-2 efficacy in rat femoral defect healing.
abstract: Bone morphogenetic proteins (BMP) have been used successfully by orthopedic clinicians to augment bone healing. However, these osteoinductive proteins must be applied at high concentrations to induce bone formation. The limited therapeutic efficacy may be due to the local expression of BMP antagonists such as Noggin that neutralize exogenous and endogenous BMPs. If so, inhibiting BMP antagonists may provide an attractive option to augment BMP induced bone formation. The engineered BMP-2 variant L51P is deficient in BMP receptor type I binding, but maintains its affinity for BMP receptor type II and BMP antagonists including Noggin, Chordin and Gremlin. This modification makes L51P a BMP receptor-inactive inhibitor of BMP antagonists. We implanted β-tricalcium phosphate ceramics loaded with BMP-2 and/or L51P into a critical size defect model in the rat femur to investigate whether the inhibition of BMP antagonist with L51P enhances the therapeutic efficacy of exogenous BMP-2. Our study reveals that L51P reduces the demand of exogenous BMP-2 to induce bone healing markedly, without promoting bone formation directly when applied alone.
authors: Department of Orthopedic Surgery, Inselspital, Bern University Hospital, CH-3010 Bern, Switzerland.
authors: Hans-Jörg
authors: HJ
authors: Sebald
authors: Frank M
authors: FM
authors: Klenke
authors: Mark
authors: M
authors: Siegrist
authors: Christoph E
authors: CE
authors: Albers
authors: Walter
authors: W
authors: Sebald
authors: Wilhelm
authors: W
authors: Hofstetter
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002130:Calcium Phosphates / Q000494:pharmacology; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology*; D007700:Kinetics; D050505:Mutant Proteins / Q000494:pharmacology*; D010012:Osteogenesis / Q000187:drug effects; D015202:Protein Engineering; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D055396:Bone Morphogenetic Protein 2; D002130:Calcium Phosphates; D050505:Mutant Proteins; C485817:beta-tricalcium phosphate