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J Bone Miner Res. 2014 Sep;29(9):1950-9. doi: 10.1002/jbmr.2238.

An activin A/BMP2 chimera, AB204, displays bone-healing properties superior to those of BMP2.

Author information

1
Protein Engineering Laboratory, Joint Center for Biosciences at Songdo Global University Campus, Incheon, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.

Abstract

Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10-fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2-like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100-fold greater than that of BMP2. The structure also led to our identification of a single Activin A-derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non-union bone fractures.

KEYWORDS:

AB204; ACTIVIN A/BMP2 CHIMERA; BONE HEALING; CRITICAL SIZE DEFECT; OSTEOGENESIS

PMID:
24692083
PMCID:
PMC4276739
DOI:
10.1002/jbmr.2238
[Indexed for MEDLINE]
Free PMC Article

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