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J. Biol. Chem., Vol. 280, Issue 24, 22907-22916, June 17, 2005

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Prostaglandin E₂ Stimulates Fibronectin Expression through EP₁ Receptor, Phospholipase C, Protein Kinase C, and c-Src Pathway in Primary Cultured Rat Osteoblasts^*

Chih-Hsin Tang, Rong-Sen Yang¶, and Wen-Mei Fu||

From the Departments of Pharmacology and Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan 100

Fibronectin (Fn) is involved in the early stages of bone formation, and prostaglandin E (PGE) is an important factor regulating osteogenesis. Here we found that PGE₂ enhanced extracellular Fn assembly in rat primary osteoblasts, as shown by immunofluorescence staining and enzyme-linked immunosorbent assay. PGE₂ also increased the protein levels of Fn by using Western blotting analysis. By using pharmacological inhibitors or activators or genetic inhibition by the EP receptor, antisense oligonucleotides revealed that the EP₁ receptor but not other PGE receptors is involved in PGE₂-mediated up-regulation of Fn. At the mechanistic level, Ca²⁺ chelator (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)), phosphatidylinositol-phospholipase C inhibitor (U73122), or Src inhibitor (PP2) attenuated the PGE₂-induced Fn expression. Protein kinase C (PKC) inhibitor (GF109203X) also inhibited the potentiating action of PGE₂. Furthermore, treatment with antisense oligonucleotides of various PKC isoforms, including , , , and , demonstrated that isozyme plays an important role in the enhancement action of PGE₂ on Fn assembly. Flow cytometry and reverse transcription-PCR showed that PGE₂ and 17-phenyl trinor PGE₂ (EP₁/EP₃ agonist) increased the surface expression and mRNA level of 5 or 1 integrins. Fn promoter activity was enhanced by PGE₂ and 17-phenyl trinor PGE₂ in cells transfected with pGL2F1900-Luc. Cotransfection with dominant negative mutants of PKC or c-Src inhibited the potentiating action of PGE₂ on Fn promoter activity. Local administration of PGE₂ or 17-phenyl trinor PGE₂ into the metaphysis of the tibia via the implantation of a needle cannula significantly increased the Fn and 51 integrin immunostaining and bone volume of secondary spongiosa in tibia. Taken together, our results provided evidence that PGE₂ increased Fn and promoted bone formation in rat osteoblasts via the EP₁/phospholipase C/PKC/c-Src signaling pathway.

Received for publication, January 5, 2005 , and in revised form, March 25, 2005.

^* This work was supported by grants from National Science Council. 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.

^¶ To whom correspondence may be addressed: Dept. of Orthopaedics, National Taiwan University Hospital, No. 7, Chung-Shan South Rd., Taipei, Taiwan. E-mail: yang{at}ha.mc.ntu.edu.tw. || To whom correspondence may be addressed: Dept. of Pharmacology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Rd., Taipei, Taiwan. Tel.: 886-2-23123456 (ext. 8319); Fax: 886-2-23417930; E-mail: wenmei{at}ha.mc.ntu.edu.tw.

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