title: BMP9 a possible alternative drug for the recently withdrawn BMP7?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.
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Vrinda
authors.initials: V
authors.lastname: Sreekumar
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Romina Haydeé
authors.initials: RH
authors.lastname: Aspera-Werz
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Gauri
authors.initials: G
authors.lastname: Tendulkar
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Marie Karolina
authors.initials: MK
authors.lastname: Reumann
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Freude
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pscherer
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Björn Gunnar
authors.initials: BG
authors.lastname: Ochs
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Flesch
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Valeska
authors.initials: V
authors.lastname: Hofmann
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
authors.forename: Andreas Klaus
authors.initials: AK
authors.lastname: Nussler
authors.affiliation: Siegfried Weller Institute for Trauma Research at the BG Trauma Center, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany. sabrina.ehnert@med.uni-tuebingen.de.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ehnert
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D056737:Safety-Based Drug Withdrawals; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D055427:Growth Differentiation Factor 2; D053244:Osteoprotegerin; D053245:RANK Ligand; D011994:Recombinant Proteins; C505688:TNFSF11 protein, human; D051153:Wnt Proteins; D000469:Alkaline Phosphatase
keywords: Alk6; BAMBI; Endoglin; Osteoblasts; Osteoclasts; SOST; Smurfs; rhBMPs