Although commercial human bone morphogenetic protein 2 (BMP-2) creates a huge revenue of nearly half a billion USD per year, there are still many unknowns in respect to its possible intrinsic functions and especially in respect to its mechanisms of action in the human body. One such unknown function, which we recently detected, is its direct influence on blood vessel formation and inhibition [1].
       Recombinant human bone morphogenetic protein 2 exists in two different species a glycosylated species from CHO-cells (rhBMP-2_CHO) and a non-glycosylated species from E. coli (rhBMP-2_COL). Both are known for their pro-osteogenic properties. rhBMP-2_CHO is clinically approved for inducing bone in fracture therapy in micromolar concentrations. In non-human mammals in vivo and in mono-cell cultures in vitro both species of rhBMP-2 have indistinguishable biological activities in nanomolar concentrations (Kr'_D ~ 2-10 nM).
       Recently we detected a new picomolar angiogenic activity of rhBMP-2_COL in co-cultures of human outgrowth endothelial cells (OECs) and human primary osteoblasts (pOBs) by employing rhBMP-2_COL adsorbate PDLLA biohybrids. For preparing such solid state biohybrids the growth factor rhBMP-2_COL was adsorbed to the surface of non-woven fleeces composed of PDLLA nanofibers (ca 100 nm in diame¬ter) by electrospinning [2]. From release-kinetic experiments rhBMP-2_COL, with a sustained release half-life of ca. 208 days, and corresponding adsorption kinetics a dissociation constant in the picomolar range of K'_D= 0.59 pM could be calculated, indicating local picomolar release concentrations (pico-stat) in cell cultures.
       In co-cultures of OECs and pOBs with biohydrids loaded with 0.33 mg rhBMP-2/g PDLLA capillary–like micro-vessels of total length 23.9 mm were induced in 14 days. Increasing the amount of adsorbed rhBMP- 2_COL ca. 8-fold to 2.6 mg/g paradoxically reduced the amount of induced micro-vessels by 80% (inverse concentration behavior). The solid state experiments were confirmed by dose response experiments in solution which also yielded affinities in the picomolar range. We conclude that rhBMP-2_COL inhibits angiogenesis in cocultures at high concentrations > 100 pM and induces micro-vessels at low concentrations < 100 pM, possibly, as a result of rhBMP-2_COL binding to a novel type of high affinity cell receptors in the co-culture.

References

[1] Dohle, E., Sowislok, A., Ghanaati, S., & Jennissen, H. P. (2021) Angiogenesis by BMP-2-PDLLA-Biohybrids in Co-Culture with Osteoblasts and Endothelia.
     Curr. Dir. Biomed. Engineer., 7, 835-838 (doi:10.1515/cdbme-2021-2213).
[2] Sowislok, A. & Jennissen, H. P. (2022) Bioengineering of Tubes, Rings and Panels for Guided Bone and Vascular Regeneration. Curr. Dir. Biomed. Engineer., 8,
     620-623 (doi.org/10.1515/cdbme-2022-1158).