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1 Divisions of Endocrinology and 2 Nephrology, Department of Internal Medicine, and 3 Cell and Developmental Biology Graduate Group, University of California, Davis 95616; and 4 Department of Veterans Affairs, Northern California Health Care System, Mather, California 95655
Bone-morphogenetic proteins (BMP)-2 and
-7, multifunctional members of the transforming growth factor (TGF)-
superfamily with powerful osteoinductive effects, cause cell cycle
arrest in a variety of transformed cell lines by activating signaling cascades that involve several cyclin-dependent kinase inhibitors (CDKIs). CDKIs in the cip/kip family, p21Cip1/Waf1 and
p27Kip1, have been shown to negatively regulate the G1
cyclins and their partner cyclin-dependent kinase proteins, resulting
in BMP-mediated growth arrest. Bone morphogens have also been
associated with antiproliferative effects in vascular tissue by unknown
mechanisms. We now show that BMP-2-mediated inhibition of
platelet-derived growth factor (PDGF)-stimulated human aortic smooth
muscle cell (HASMC) proliferation is accompanied by increased levels of
p21 protein. Antisense oligodeoxynucleotides specific for p21 attenuate BMP-2-induced inhibition of proliferation when transfected into HASMCs,
demonstrating that BMP-2 inhibits PDGF-stimulated proliferation of
HASMCs through induction of p21. Whether p21-mediated induction of cell
cycle arrest by BMP-2 sets the stage for osteogenic differentiation of
vascular smooth muscle cells, ultimately leading to vascular mineralization, remains to be investigated.
bone morphogenetic protein-2; vascular smooth muscle cell; antisense
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