| RRC ID |
43017
|
| 著者 |
Tang CH, Lu DY, Tan TW, Fu WM, Yang RS.
|
| タイトル |
Ultrasound induces hypoxia-inducible factor-1 activation and inducible nitric-oxide synthase expression through the integrin/integrin-linked kinase/Akt/mammalian target of rapamycin pathway in osteoblasts.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
It has been shown that ultrasound (US) stimulation accelerates fracture healing in the animal models and clinical studies. Nitric oxide (NO) is a crucial early mediator in mechanically induced bone formation. Here we found that US stimulation increased NO formation and the protein level of inducible nitric-oxide synthase (iNOS). US-mediated iNOS expression was attenuated by anti-integrin alpha5beta1 or beta1 antibodies but not anti-integrin alphavbeta3 or beta3 antibodies or focal adhesion kinase mutant. Integrin-linked kinase (ILK) inhibitor (KP-392), Akt inhibitor (1L-6-hydroxymethyl-chiro-inositol-2-[(R)-2-O-methyl-3-O-octadecylcarbonate]) or mammalian target of rapamycin (mTOR) inhibitor (rapamycin) also inhibited the potentiating action of US. US stimulation increased the kinase activity of ILK and phosphorylation of Akt and mTOR. Furthermore, US stimulation also increased the stability and activity of HIF-1 protein. The binding of HIF-1alpha to the HRE elements on the iNOS promoter was enhanced by US stimulation. Moreover, the use of pharmacological inhibitors or genetic inhibition revealed that both ILK/Akt and mTOR signaling pathway were potentially required for US-induced HIF-1alpha activation and subsequent iNOS up-regulation. Taken together, our results provide evidence that US stimulation up-regulates iNOS expression in osteoblasts by an HIF-1alpha-dependent mechanism involving the activation of ILK/Akt and mTOR pathways via integrin receptor.
|
| 巻・号 |
282(35)
|
| ページ |
25406-15
|
| 公開日 |
2007-8-31
|
| DOI |
10.1074/jbc.M701001200
|
| PII |
S0021-9258(20)74614-4
|
| PMID |
17588951
|
| MeSH |
Animals
Antibodies / pharmacology
Cell Line
Disease Models, Animal
Focal Adhesion Kinase 1 / antagonists & inhibitors
Focal Adhesion Kinase 1 / metabolism
Fracture Healing / physiology
Fractures, Bone / enzymology
Fractures, Bone / pathology
Fractures, Bone / therapy
Gene Expression Regulation, Enzymologic / drug effects
Hypoxia-Inducible Factor 1, alpha Subunit
Integrin alpha5beta1 / antagonists & inhibitors
Integrin alpha5beta1 / metabolism
Integrin alphaVbeta3 / antagonists & inhibitors
Integrin alphaVbeta3 / metabolism
Mice
Nitric Oxide / biosynthesis
Nitric Oxide Synthase Type II / biosynthesis*
Osteoblasts / enzymology*
Osteoblasts / pathology
Protein Binding / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Kinases / metabolism*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism*
Response Elements
Signal Transduction / drug effects
Sonication*
TOR Serine-Threonine Kinases
Up-Regulation / drug effects
|
| IF |
4.238
|
| 引用数 |
57
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
MC3T3-E1(RCB1126) |
