The osteogenic and angiogenic properties of different bone morphogenetic proteins: a delicate balance
(2012) 9th International Conference on Bone Morphogenetic Proteins — Location: Lake Tahoe, USA (19.June.2012)
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- Abstract
- Bone morphogenetic proteins (BMPs) hold great promise for bone regeneration applications. BMP technology however requires that the microenvironment is not manifestly compromised by limited numbers of responsive cells (for example in older patients) or lack of adequately perfused blood vessels. Therefore, the combination of BMPs with osteogenic progenitor cells might mimic more closely the natural bone repair process than the use of solely a BMP. The aim of this study was to compare the effect of different BMPs (BMP-2, -4, -6, -7 and -9) on osteogenic differentiation of periosteum-derived cells (PDC), a clinically relevant osteogenic cell source. As several studies have indicated that BMP signaling is also involved in the process of blood vessel formation, we additionally evaluated the potential of different BMPs to enhance angiogenic growth factor production by the PDC, as well as the direct effects of BMPs on endothelial cells. First, different BMPs (concentrations ranging from 1-100 ng/ml) were added during osteogenic differentiation of murine PDC (mPDC). Staining for alkaline phosphatase after 6 days and for mineralization with Alizarin Red after 12 days revealed that BMP-9 had the strongest positive effect, followed by BMP-4 and BMP-2, while BMP-6 and BMP-7 only had a minor influence. Quantitative RT-PCR analysis confirmed that only BMP-9 (10 or 100 ng/ml) and BMP-4 (100 ng/ml) induced very strong upregulation of Runx2 and Osteocalcin gene expression levels compared to cells in osteogenic medium without BMP addition. In addition, BMP-9 significantly enhanced the expression of angiogenic factors such as Vegf, Fgf2 and Tgfb1 by mPDC, while BMP-4 exerted a positive effect only on Fgf2 expression. When added during short-term cultures of human umbilical vein endothelial cells (HUVEC) on matrigel, BMP-9 increased branching and network formation. In contrast, BMP-9 severely reduced cell numbers during longer cultures on collagen gels. Measurement of BrdU incorporation showed that BMP-9 impaired the proliferation of HUVEC, even at lower doses. BMP-4 in comparison enhanced network formation by HUVEC during short cultures on matrigel and did not influence endothelial cell proliferation. Taken together, our data show that both BMP-4 and BMP-9 significantly increase the osteogenic and pro-angiogenic potential of PDC. The positive effect of BMP-4 on angiogenic cells further suggests that a low dose of BMP-4 in combination with periosteal cells might be an ideal strategy to promote bone regeneration. On the other hand, care should be taken when applying BMP-9 in vivo, as it exerts opposing effects on osteogenic and endothelial cells.
- Affiliations
KU Leuven Laboratory of Clinical and Experimental Endocrinology KU Leuven Prometheus, Division of Skeletal Tissue Engineering
Citations
van Gastel, N., Stockmans, I., Schrooten, J., Luyten, F. P., & Carmeliet, G. (2012). The osteogenic and angiogenic properties of different bone morphogenetic proteins: a delicate balance. 9th International Conference on Bone Morphogenetic Proteins, Lake Tahoe, USA. https://hdl.handle.net/2078.5/109490