Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro.
Vascular proliferative disorders are characterized by migration and proliferation of vascular smooth muscle cells (SMCs), loss of expression of SMC phenotype, and enhanced extracellular matrix synthesis (e.g., type I collagen). We report here that bone morphogenetic protein-7 (BMP-7), a member of the transforming growth factor-beta (TGF-beta) superfamily, is capable of inhibiting both serum-stimulated and growth factor-induced (platelet-derived growth factor [PDGF-BB] and TGF-beta1) cell growth as measured by (3)H-thymidine uptake into DNA synthesis and cell number in primary human aortic smooth 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 during PDGF-BB-induced proliferation of SMCs and upregulates the expression of the inhibitory Smad, Smad6, which was shown to inhibit TGF-beta superfamily signaling. These results collectively suggest that BMP-7 maintains the expression of vascular SMC phenotype and may prevent vascular proliferative disorders, thus potentially acting as a palliative after damage to the vascular integrity.
Dorai
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Creative BioMolecules Inc., Hopkinton, Massachusetts, USA. hdorai@creativebio.com
Vukicevic
S
S
Sampath
T K
TK
D000199:Actins / Q000235:genetics; D001011:Aorta; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D055419:Bone Morphogenetic Protein 7; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology
D000199:Actins; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D000077214:Becaplermin; D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D018995:Myosin Heavy Chains