BMP9 a possible alternative drug for the recently withdrawn BMP7? New perspectives for (re-)implementation by personalized medicine

Abstract

Promotion of rhBMP2 and rhBMP7 for the routine use to support fracture healing has been hampered by high costs, safety concerns and reasonable failure rates, imposing restrictions in its clinical use. Since there is little debate regarding its treatment potential, there is rising need for a better understanding of the mode of action of these BMPs to overcome its drawbacks and promote more efficacious treatment strategies for bone regeneration. Recently, BMP9, owing to its improved osteogenic potential, is gaining attention as a promising therapeutic alternative. Our study aimed at identifying specific gene expression patterns which may predict and explain individual responses to rhBMP7 and rhBMP9 treatments. Therefore, we investigated the effect of rhBMP7 and rhBMP9 on primary human osteoblasts from 110 donors and corresponding THP-1-derived osteoclasts. This was further compared with each other and our reported data on rhBMP2 response. Based on the individual donor response, we found three donor groups profiting from rhBMP treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclasts. The response on rhBMP7 treatment correlated with expression levels of the genes BAMBI, SOST, Noggin, Smad4 and RANKL, while the response of rhBMP9 correlated to the expression levels of Alk6, Endoglin, Smurf1, Smurf2, SOST and RANKL in these donors. Noteworthy, rhBMP9 treatment showed significantly increased osteogenic activity (AP activity and Smad nuclear translocation) when compared to the two clinically used rhBMPs. Based on patient's respective expression profiles, clinical application of rhBMP9 either solely or in combination with rhBMP2 and/or rhBMP7 can become a promising new approach to fit the patient's needs to promote fracture healing.

BMP-9 interferes with liver regeneration and promotes liver fibrosis

“…Whereas inhibition of BMP-9/ALK1 signalling is already discussed as a potential anti-angiogenic strategy in cancer46 and clinical application of rhBMP-9 was recently presented as a potentially promising new approach to promote fracture healing,47 its possible roles during acute or chronic liver damage were only insufficiently investigated up to now. In the present work, we therefore addressed this point and investigated BMP-9 expression levels, cellular responses and in vivo consequences of BMP-9 signalling in liver cells in vitro as well as in diverse mouse models for acute and chronic liver damage.…”

Novel Natural Bovine Bone Graft with Integrated Atelo-Collagen Type I: Atelocollagen Bovine Bone Mineral (ABBM) Characterization In-vivo

“…Furthermore, no foreign body reaction was observed in any of the 6 animals and it may therefore be concluded that the material is well-suited to regenerate new bone with much further potential for future research and clinical applications. Future research is therefore eminently needed to compare the regenerative potential of ABBM versus some of the leaders in the bone grafting field [28][29][30].…”

From the Clinical Problem to the Basic Research—Co-Culture Models of Osteoblasts and Osteoclasts

“…This permeable barrier can either be a removable permeable divider [49] or a transwell system [50]. When the effect of one special cell type on another cell type is investigated without the physiological feedback, transfer of conditioned medium from one cell type to another is a feasible option [51,52]. In the same line, one type of cells can be seeded onto an extracellular matrix (ECM) that has been produced by another type of cells [53].…”

“…Thus, in a co-culture approach, no additional cytokines should be needed. Simply by using the conditioned medium of differentiating primary osteoblasts, mononuclear cells can be differentiated into osteoclastic cells [51,52]. On the other hand, to avoid diverse supplements from interfering with the differentiation process of the other cell type in co-culture, Schulze presented a direct co-culture model of human B-MSCs and PBMCs without exogenous cytokines, which is suitable to mimic bone-remodeling [110].…”