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J. Biol. Chem., Vol. 282, Issue 35, 25406-25415, August 31, 2007

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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^*

Chih-Hsin Tang, Dah-Yuu Lu, Tzu-Wei Tan, Wen-Mei Fu¹, and Rong-Sen Yang^¶2

From the Department of Pharmacology, College of Medicine, China Medical University, Taichung 404 and the Departments ofPharmacology and ^¶Orthopaedics, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100, Taiwan

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 51 or 1 antibodies but not anti-integrin v3 or 3 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-1 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-1 activation and subsequent iNOS up-regulation. Taken together, our results provide evidence that US stimulation up-regulates iNOS expression in osteoblasts by an HIF-1-dependent mechanism involving the activation of ILK/Akt and mTOR pathways via integrin receptor.

Received for publication, February 2, 2007 , and in revised form, June 19, 2007.

^* This work was supported by the National Science Council of Taiwan (Grant NSC 95-2314-B-039-045) and China Medical University (Grant CMU 95-208). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed: Tel.: 886-2-231-23456 (ext. 8319); Fax: 886-2-23417930; E-mail: wenmei{at}ntu.edu.tw. ² To whom correspondence may be addressed: Tel.: 886-2-231-23456 (ext. 3958); Fax: 886-2-239-36577; E-mail: rsyang{at}ntuh.gov.tw.

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