BMP-2 inhibits proliferation of human aortic smooth muscle cells via p21Cip1/Waf1.
Bone-morphogenetic proteins (BMP)-2 and -7, multifunctional members of the transforming growth factor (TGF)-beta 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, p21(Cip1/Waf1) and p27(Kip1), 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.
Wong
Gail A
GA
Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition and Vascular Medicine, University of California-Davis, UC Davis Medical Center, 4150 V Street, PSSB G400, Sacramento, CA 95817, USA. gawong@ucdavis.edu
Tang
Vincent
V
El-Sabeawy
Faten
F
Weiss
Robert H
RH
D001011:Aorta / Q000166:cytology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016376:Oligonucleotides, Antisense; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta