A novel role of bone morphogenetic protein-7 in the regulation of adhesion and migration of human monocytic cells. Issue 147 (November 2016)

• Record Type: Journal Article
• Authors: Sovershaev, T.A.; Unruh, D.; Sveinbjørnsson, B.; Fallon, J.T.; Hansen, J.B.; Bogdanov, V.Y.; Sovershaev, M.A.
• Is Part Of: Thrombosis research. Issue 147(2016)
• Page Start: 24
• Page End: 31
• Publication Date: 2016-11
• Subjects: Atherosclerosis -- Bone morphogenetic proteins -- Monocytes -- Cell migration; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2016.09.018
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: 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. Aims: 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. Conclusion: 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. Highlights: BMP-7 enhances all steps of monocyte extravasation. BMP-7 activates the Akt-FAK signalling pathway in human monocytes. Inhibitors of BMP signalling abrogate BMP-7′s effects on monocyte motility.