Establishment of the premises for using the pro-form of bone morphogenetic protein (BMP-2) as a therapeutic tool

Bone morphogenetic protein (BMP-2) is in clinical use since 2002. Clinical indications are mainly slow healing fractures. Recently, the administration of BMP-2 has been reported to be accompanied by adverse side effects. Since in our studies significantly lower doses of BMP-2 than those applied in the clinic had induced ectopic bone formation, the side effects may be due to insufficient doses adjustment. For the related transforming growth factor-b (TGF-b), a latency conferring role of the pro-peptide has been demonstrated. Our own data indirectly suggest that the pro-peptide of BMP-2 may retard the activity of the mature growth factor. Thus, proBMP-2 may be a late acting therapeutic protein by which overdoses effects may be intrinsically counteracted by the pro-peptide.
The objective of the proposal is testing the premises for administration of proBMP-2 as a novel, delayed acting drug for bone regeneration. The following subtopics will be dealt with: Optimization of recombinant production and refolding of authentic proBMP-2, analysis of the effect of carrier materials (for in vivo delivery) and spin labels (for in vivo monitoring) on structure and function of the protein, determination of growth factor release from the carrier material and determination of the biological responses elicited by proBMP-2.