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J. Biol. Chem., Vol. 283, Issue 16, 10835-10847, April 18, 2008

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Transforming Growth Factor-β1 (TGFβ1) Stimulates Connective Tissue Growth Factor (CCN2/CTGF) Expression in Human Gingival Fibroblasts through a RhoA-independent, Rac1/Cdc42-dependent Mechanism

STATINS WITH FORSKOLIN BLOCK TGFβ1-INDUCED CCN2/CTGF EXPRESSION^*

From the Department of Periodontology and Oral Biology, Division of Oral Biology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts 02118

Regulation of connective tissue growth factor (CCN2/CTGF) in gingival fibroblasts is unique and may provide therapeutic opportunities to treat oral fibrotic diseases. RhoA was previously implicated in mediating the expression of CCN2/CTGF. We now present evidence that Rho family GTPases Rac1 and Cdc42 are the principal mediators of the transforming growth factor-β1 (TGFβ1)-stimulated expression of CCN2/CTGF in primary human gingival fibroblasts. TGFβ1 does not stimulate RhoA activation in gingival fibroblasts, and the overexpression of dominant-negative RhoA does not reduce CCN2/CTGF expression in response to TGFβ1. In contrast, the overexpression of dominant-negative forms of Cdc42 or Rac1 results in a dramatic reduction of CCN2/CTGF protein levels. Lovastatin and a geranylgeranyltransferase inhibitor reduce the TGFβ1-stimulated levels of CCN2/CTGF protein by 75 and 100%, respectively. We previously demonstrated that JNK1 phosphorylation by TGFβ1 is also critical for TGFβ1-induced CCN2/CTGF expression, and forskolin partially reduces levels of phosphorylated JNK1. Inhibition of geranylgeranyltransferase has no effect on levels of JNK phosphorylation in response to TGFβ1 suggesting Rho-GTPases act independently of JNK1. The combination of lovastatin and forskolin results in a greater inhibitory effect than each agent alone and reduces CCN2/CTGF mRNA and protein expression by greater than 90%. This novel combination has additive inhibitory effects on the TGFβ1-stimulated expression of CCN2/CTGF in human gingival fibroblasts through the simultaneous disruption of Rho- and JNK1-mediated pathways, respectively. This combination of available therapeutic compounds may therefore be useful in designing treatment strategies for oral fibrotic conditions in which gingival CCN2/CTGF is elevated.

Received for publication, December 19, 2007 , and in revised form, February 7, 2008.

^* This work was supported by National Institutes of Health NIDCR Grants R01 DE11004, K08 DE016609, and M01 RR00533. 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.

¹ To whom correspondence should be addressed: Boston University Goldman School of Dental Medicine, Dept. of Periodontology and Oral Biology, Division of Oral Biology, 700 Albany St., Boston, MA 02118. Tel.: 617-638-4076; Fax: 617-638-5265; E-mail: trackman{at}bu.edu.

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