Osteoblast-like differentiation of cultured human coronary artery smooth muscle cells by bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER).
Differentiation of vascular smooth muscle cells (SMCs) into osteoblast-like cells is considered to be a mechanism of vascular calcification. However, regulators of osteoblast-like differentiation of vascular SMCs are not fully elucidated. Here, we investigated the expression of bone morphogenetic protein (BMP)-binding endothelial cell precursor-derived regulator (BMPER), a vertebrate homologue of Drosophila crossveinless-2, in vascular SMCs and the role and mode of action of BMPER in osteoblast-like differentiation of human coronary artery SMCs (HCASMCs). BMPER was expressed in cultured human vascular SMCs, including HCASMCs. Silencing of endogenous BMPER expression by an RNA interference technique inhibited osteoblast-like differentiation of HCASMCs, as evaluated by up-regulation of osteoblast markers such as alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), by down-regulation of a SMC marker α-smooth muscle actin (αSMA), and by mineralization. Treatment with recombinant BMPER enhanced, whereas BMP-2 reduced osteoblast-like differentiation. BMPER antagonized BMP-2-induced phosphorylation of Smad 1/5/8, suggesting that the effect of BMPER was mediated by antagonizing the action of BMP. BMPER increased IκBα phosphorylation and NF-κB activity and specific NF-κB decoy oligonucleotides deteriorated osteoblast-like differentiation of HCASMCs by BMPER. In human coronary artery with atherosclerotic plaque containing calcification, the BMPER-positive signals were observed in the neointimal and medial SMCs in the vicinity of the plaque. These findings indicate that BMPER is a novel regulator of the osteoblast-like differentiation of HCASMCs.
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan.
Seimi
S
Satomi-Kobayashi
Mitsuo
M
Kinugasa
Reiko
R
Kobayashi
Kinta
K
Hatakeyama
Yusuke
Y
Kurogane
Tatsuro
T
Ishida
Noriaki
N
Emoto
Yujiro
Y
Asada
Yoshimi
Y
Takai
Ken-ichi
K
Hirata
Yoshiyuki
Y
Rikitake
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D000199:Actins; C525718:BMP2 protein, human; C476724:BMPER protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D020672:I-kappa B Proteins; D016328:NF-kappa B; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; C517553:crossveinless 2 protein, mouse