(Circulation. 2000;102:2636.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Tumor Necrosis Factor-
Promotes In Vitro Calcification of Vascular Cells via the cAMP Pathway
From the Division of Cardiology, Departments of Medicine and Physiology, UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Yin Tintut, Division of Cardiology, UCLA School of Medicine, 47-123 Center for the Health Sciences, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail ytintut{at}ucla.edu
Background—Vascular calcification
is an ectopic calcification that commonly occurs in
atherosclerosis. Because tumor necrosis factor-
(TNF-), a pleiotropic cytokine found in atherosclerotic
lesions, is also a regulator of bone formation, we investigated the
role of TNF- in in vitro vascular calcification.
Methods and Results—A cloned subpopulation of bovine aortic
smooth muscle cells previously shown capable of osteoblastic
differentiation was treated with TNF-, and osteoblastic
differentiation and mineralization were assessed. Treatment of vascular
cells with TNF- for 3 days induced an osteoblast-like morphology. It
also enhanced both activity and mRNA expression of alkaline
phosphatase, an early marker of osteoblastic differentiation.
Continuous treatment with TNF- for 10 days enhanced matrix
mineralization as measured by radiolabeled calcium incorporation in the
matrix. Pretreatment of cells with a protein kinase A–specific
inhibitor, KT5720, attenuated cell morphology, the alkaline
phosphatase activity, and mineralization induced by TNF-.
Consistent with this, the intracellular cAMP level was elevated
after TNF- treatment. Electrophoretic mobility shift assay
demonstrated that TNF- enhanced DNA binding of osteoblast specific
factor (Osf2), AP1, and CREB, transcription factors that are important
for osteoblastic differentiation.
Conclusions—These results suggest that TNF- enhances in vitro
vascular calcification by promoting osteoblastic differentiation of
vascular cells through the cAMP pathway.
Key Words: muscle, smooth • signal transduction • atherosclerosis
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