Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth musclecell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro

Vascular proliferative disorders are characterized by migration and prolife ration of vascular smooth muscle cells (SMCs), loss of expression of SMC ph enotype, and enhanced extracellular matrix synthesis (e.g., type I collagen ). We report here that bone morphogenetic protein-7 (BMP-7), a member of th e transforming growth factor-beta (TCF-beta) superfamily, is capable of inh ibiting both serum-stimulated and growth factor-induced (platelet-derived g rowth factor [PDCF-BB] and TGF-beta 1) cell growth as measured by H-3-thymi dine uptake into DNA synthesis and cell number in primary human aortic smoo th muscle (HASM) cell cultures. Concomitantly, addition of BMP-7 stimulates the expression of SMC-specific markers, namely alpha-actin and heavy chain myosin as examined by RT-PCR and Northern blot analyses. The collagen type III/I ratio that becomes lower with the transdifferentiation of SMCs into myofibroblasts is also maintained in BMP-7-treated cultures as compared to untreated controls. Studies on the mechanism of action indicate that BMP-7 treatment inhibits cyclin-dependent kinase 2 (cdk-2) that was stimulated du ring PDGF-BB-induced proliferation of SMCs and upregulates the expression o f the inhibitory Smad, Smad6, which was shown to inhibit TGF-beta superfami ly signaling. These results collectively suggest that BMP-7 maintains the e xpression of vascular SMC phenotype and may prevent vascular proliferative disorders, thus potentially acting as a palliative after damage to the vasc ular integrity. J. Cell. Physiol. 184:37-45, 2000. (C) 2000 Wiley-Liss, Inc .