BMP9 a possible alternative drug for the recently withdrawn BMP7?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

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.

Distinct Gene Expression Patterns Defining Human Osteoblasts' Response to BMP2 Treatment: Is the Therapeutic Success All a Matter of Timing?

BACKGROUND: Bone morphogenetic proteins (BMPs) play a key role in bone formation. Local application of BMP2 (Dibotermin alfa) supports bone formation when applied to complex fractures. However, up to 33% of patients do not respond to this therapy. PURPOSE: Aiming to investigate whether inter-individual responses to BMP2 treatment can be predicted by gene expression patterns, we investigated the effect of BMP2 on primary human osteoblasts and THP-1 cell-derived osteoclasts from 110 donors. METHODS: Osteoblasts were obtained by collagenase digestion of spongy bone tissues. Osteoclasts were differentiated from THP-1 cells using the conditioned media of the osteoblasts. Viability was determined by resazurin conversion. As functional characteristics AP and Trap5B activity were measured. Gene expression levels were determined by RT-PCR in 21 of the 110 evaluated donors and visualized by electrophoresis. RESULTS: Based on our data, we could classify three response groups: (i) In 51.8% of all donors, BMP2 treatment induced osteoblast function. These donors strongly expressed the BMP2 inhibitor Noggin (NOG), the alternative BMP2 receptors repulsive guidance molecule B (RGMb) and activin receptor-like kinase 6 (Alk6), as well as the Wnt inhibitor sclerostin (SOST). (ii) In 17.3% of all donors, BMP2 treatment induced viability. In these donors, the initial high SOST expression significantly dropped with BMP2 treatment. (iii) 30.9% of all donors were not directly affected by BMP2 treatment. These donors expressed high levels of the pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) and lacked SOST expression. In all donors, SOST expression correlated directly with receptor activator of NF-κB ligand (RANKL) expression, defining the cells' potential to stimulate osteoclastogenesis. CONCLUSIONS: Our data identified three donor groups profiting from BMP2 treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclastogenesis, depending on their expression of BAMBI, SOST, NOG, and RANKL. On the basis of patients' respective expression profiles, the clinical application of BMP2 as well as its timing might be modified in order to better fit the patients' needs to promote bone formation or to inhibit bone resorption.