A novel role of bone morphogenetic protein-7 in the regulation of adhesion and migration of human monocytic cells.
BACKGROUND
Bone morphogenetic protein (BMP) 7 is abundant in atherosclerotic plaques and increases monocyte pro-coagulant activity by enhancing tissue factor (TF) expression. While several members of the BMP superfamily are able to serve as chemotactic agents for monocytes, the role of BMP-7 in regulation of monocyte motility is not known.


OBJECTIVE
To assess the effect of BMP-7 on adhesive and migratory properties of human monocytes.


METHODS
Chemokinesis, adhesion, and transendothelial migration of BMP-7-treated THP-1 cells and human monocytes were analysed using live-cell imaging, orbital shear, and Boyden chamber assays. Surface presentation of β2 integrins and phosphorylation status of Akt & focal adhesion kinase (FAK) were studied by flow cytometry and Western blot.


RESULTS
High levels of BMP-7 protein were detectable in intimal regions of atherosclerotic plaques; BMP-7 significantly enhanced THP-1 and monocyte chemokinetic properties in vitro (1.21+0.01 and 1.76+0.21 fold increase in crawling distance, respectively). Under orbital shear, adhesion of monocytic cells to microvascular endothelial cell (MVEC) monolayers was also significantly increased by BMP-7 (3.89+1.56 and 2.57+0.97 fold over vehicle). Moreover, BMP-7 accelerated transendothelial migration of THP-1 cells and monocytes towards MCP-1 (5.91+0.88 and 2.96±0.65 fold increase, respectively). BMP-7 enhanced cell surface presentation of β2 integrins in the active conformation. Observed effects were determined to be Akt and FAK dependent, as shown by pharmacological inhibition.


CONCLUSIONS
BMP-7 directly upregulates adhesion and migration of human monocytic cells via activation of β2 integrins, Akt, and FAK. Our findings suggest that BMP-7 may serve as a novel contributor to atherogenesis.
K.G. Jebsen Thrombosis and Expertise Center (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, N-9037 Tromsø, Norway.
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Sovershaev
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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Unruh
Molecular Inflammation Research Group, Department of Medical Biology, UiT - The Arctic University of Norway, N-9037 Tromsø, Norway.
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Sveinbjørnsson
Department of Pathology, Westchester Medical Center/New York Medical College, Valhalla, NY, USA.
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JT
Fallon
K.G. Jebsen Thrombosis and Expertise Center (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, N-9037 Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, N-9038 Tromsø, Norway.
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Hansen
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA. Electronic address: vladimir.bogdanov@uc.edu.
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VY
Bogdanov
Section for Medical Biochemistry, Department of Laboratory Medicine, University Hospital of Northern Norway, N-9038 Tromsø, Norway.
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Sovershaev
D050197:Atherosclerosis / Q000276:immunology; D055419:Bone Morphogenetic Protein 7 / Q000276:immunology*; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis; D051417:Focal Adhesion Kinase 1 / Q000276:immunology; D006801:Humans; D039641:Integrin beta Chains / Q000276:immunology*; D009000:Monocytes / Q000166:cytology* / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D015398:Signal Transduction
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D039641:Integrin beta Chains; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt
Atherosclerosis; Bone morphogenetic proteins; Cell migration; Monocytes