title: CCN3 increases BMP-4 expression and bone mineralization in osteoblasts.
abstract: The nephroblastoma overexpressed (NOV) gene, also called CCN3, regulates differentiation of skeletal mesenchymal cells. Bone morphogenetic proteins (BMPs) play important roles in osteoblast differentiation and bone formation, but the effects of CCN3 on BMP expression and bone formation in cultured osteoblasts are largely unknown. Here we found that CCN3 increased BMP-4 expression and bone nodule formation in cultured osteoblast. Monoclonal antibodies for α5β1 and αvβ5 integrins, and inhibitors of integrin-linked kinase (ILK), p38, and JNK, all inhibited CCN3-induced bone nodule formation and BMP-4 up-regulation of osteoblasts. CCN3 stimulation increased the kinase activity of ILK and phosphorylation of p38 and JNK. Inhibitors of activator protein-1 (AP-1) also suppressed bone nodule formation and BMP-4 expression enhanced by CCN3. Moreover, CCN3-induced c-Jun translocation into the nucleus, and the binding of c-Jun to the AP-1 element on the BMP-4 promoter were both inhibited by specific inhibitors of the ILK, p38, and JNK cascades. Taken together, our results provide evidence that CCN3 enhances BMP-4 expression and bone nodule formation in osteoblasts, and that the integrin receptor, ILK, p38, JNK, and AP-1 signaling pathways may be involved.
authors: Department of Pharmacology, School of Medicine, China Medical University and Hospital, Taichung, Taiwan.
authors: Tzu-Wei
authors: TW
authors: Tan
authors: Yuan-Lin
authors: YL
authors: Huang
authors: Jung-Tzu
authors: JT
authors: Chang
authors: Jen-Jyh
authors: JJ
authors: Lin
authors: Yi-Chin
authors: YC
authors: Fong
authors: Chien-Chung
authors: CC
authors: Kuo
authors: Chun-Hao
authors: CH
authors: Tsai
authors: Yen-Jen
authors: YJ
authors: Chen
authors: Horng-Chaung
authors: HC
authors: Hsu
authors: Der-Yang
authors: DY
authors: Cho
authors: Yi-Hung
authors: YH
authors: Chen
authors: Chih-Hsin
authors: CH
authors: Tang
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D055514:Nephroblastoma Overexpressed Protein / Q000378:metabolism*; D009841:Oligonucleotides / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D055415:Bone Morphogenetic Protein 4; D039081:Integrin alpha5beta1; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D055514:Nephroblastoma Overexpressed Protein; D009841:Oligonucleotides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun; D019030:Receptors, Vitronectin; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000099200:Scaffold Protein ILK; C525810:Bmp4 protein, mouse; C526319:CCN3 protein, human; C064660:integrin alphaVbeta5