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Bone Morphogenic Protein-7 Inhibits Monocyte-Stimulated TGF-1 Generation in Renal Proximal Tubular Epithelial Cells

Xiao Liang Zhang^*, Wisam Selbi^*, Carol de la Motte, Vincent Hascall and Aled O. Phillips^*

^* Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff Wales, United Kingdom; and Departments of; Colorectal Surgery; and Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, Ohio

Address correspondence to: Dr. Aled O. Phillips, Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN. Phone: 44-2920-748411; Fax: 44-2920-748470; PhillipsAO{at}cf.ac.uk

It has been demonstrated that bone morphogenic protein-7 (BMP-7) stimulates formation of hyaluronan (HA)-based cables on the cell surface of renal proximal tubular cells and that these cables mediate monocyte binding. Furthermore, interaction of monocytes with proximal tubule cell (PTC) surface intracellular adhesion molecule (ICAM) stimulates the synthesis of TGF-1. This study examined the effect of BMP-7 on monocyte-stimulated TGF-1 synthesis under conditions of basal and stimulated ICAM expression. Monocyte (U937 cells)-dependent stimulation of TGF-1 promoter activity and protein synthesis was reduced by addition of BMP-7 for 24 h before addition of U937 cells. Removal of cell surface HA or inhibition of monocyte interaction with HA using antibody to CD44 prevented this effect of BMP-7. These data suggest that BMP-7 enhances HA-dependent binding and reduces ICAM-dependent binding, which is known to stimulate TGF-1 synthesis. This hypothesis was examined further by stimulation of PTC ICAM expression by TNF-. After TNF- stimulation, monocyte-dependent TGF-1 synthesis increased. This was abrogated by inhibition of ICAM-CD18 interactions. TNF- stimulation alone did not increase TGF-1 synthesis. TNF- stimulation of PTC in the presence of BMP-7 failed to increase monocyte-dependent TGF-1 stimulation. Although stimulation of PTC by BMP-7 alone decreased cell surface ICAM expression, it did not affect TNF-–induced ICAM expression. The effect of BMP-7 on TGF-1 synthesis in TNF-–stimulated cells was abrogated by disruption of CD44–HA interactions, suggesting that it was due to increased monocyte binding to HA on the cell surface.

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