title: BMP2 induces osteoblast apoptosis in a maturation state and noggin-dependent manner.
abstract: Large doses of bone morphogenetic protein 2 (BMP2) are used clinically to induce bone formation in challenging bone defects. However, complications after treatment include swelling, ectopic bone formation, and adjacent bone resorption. While BMP2 can be effective, it is important to characterize the mechanism of the deleterious effects to optimize its use. The aim of this study was to determine the effect of BMP2 on apoptosis in osteoblast lineage cells and to determine the role of the BMP inhibitor Noggin in this process. Human mesenchymal stem cells (MSCs), immature osteoblast-like MG63 cells, and mature normal human osteoblasts (NHOst) were treated with BMP2. A model system of increased endogenous BMP signaling was created by silencing Noggin (shNOG-MG63). Finally, the BMP pathway regulating apoptosis in NHOst was examined using BMP signaling inhibitors (5Z-7-oxozeaenol, dorsomorphin, H-8). Apoptosis was characterized by caspase-3, BAX/BCL2, p53, and DNA fragmentation. BMP2 induced apoptosis in a cell-type dependent manner. While the effect was minor in MSCs, MG63 cells had modest increases and NHOst cells had robust increases apoptosis after BMP2 treatment. Apoptosis was significantly higher in shNOG-MG63 than MG63 cells. 5Z-7-oxozeaenol and dorsomorphin eliminated the BMP2-induced increase in DNA fragmentation in NHOst, suggesting roles for TAB/TAK1 and Smad signaling. These results indicate that the apoptotic effect of BMP2 is dependent on cell maturation state, inducing apoptosis in committed osteoblasts through Smad and TAB/TAK1 signaling, and is regulated by Noggin. Dose and delivery must be optimized in therapeutic applications of BMP2 to minimize complications.
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Hyzy
authors.forename: Rene
authors.initials: R
authors.lastname: Olivares-Navarrete
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
mesh_terms: D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D006801:Humans; D020287:In Situ Nick-End Labeling; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D000099176:Noggin Protein; D007783:Lactones; D012118:Resorcinols
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D053148:Caspase 3; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015025:Zearalenone; D051028:bcl-2-Associated X Protein; D000099176:Noggin Protein; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C494826:BAX protein, human; C525718:BMP2 protein, human; C516138:dorsomorphin; C505407:CASP3 protein, human