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J. Biol. Chem., Vol. 278, Issue 44, 43146-43156, October 31, 2003

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Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP₂ Receptor^*

Priscilla P. Cherian, Benxu Cheng, Sumin Gu, Eugene Sprague¶, Lynda F. Bonewald||, and Jean X. Jiang**

From the Department of Biochemistry and ^¶Radiology, University of Texas Health Science Center, San Antonio, Texas 78229-3900 and the ^||Department of Oral Biology, School of Dentistry, University of Missouri, Kansas City, Missouri 64108

Osteocytes embedded in the matrix of bone are thought to be mechanosensory cells that translate mechanical strain into biochemical signals that regulate bone modeling and remodeling. We have shown previously that fluid flow shear stress dramatically induces prostaglandin release and COX-2 mRNA expression in osteocyte-like MLO-Y4 cells, and that prostaglandin E₂ (PGE₂) released by these cells functions in an autocrine manner to regulate gap junction function and connexin 43 (Cx43) expression. Here we show that fluid flow regulates gap junctions through the PGE₂ receptor EP₂ activation of cAMP-dependent protein kinase A (PKA) signaling. The expression of the EP₂ receptor, but not the subtypes EP₁,EP₃, and EP₄, increased in response to fluid flow. Application of PGE₂ or conditioned medium from fluid flow-treated cells to non-stressed MLO-Y4 cells increased expression of the EP₂ receptor. The EP₂ receptor antagonist, AH6809, suppressed the stimulatory effects of PGE₂ and fluid flow-conditioned medium on the expression of the EP₂ receptor, on Cx43 protein expression, and on gap junction-mediated intercellular coupling. In contrast, the EP₂ receptor agonist butaprost, not the E₁/E₃ receptor agonist sulprostone, stimulated the expression of Cx43 and gap junction function. Fluid flow conditioned medium and PGE₂ stimulated cAMP production and PKA activity suggesting that PGE₂ released by mechanically stimulated cells is responsible for the activation of cAMP and PKA. The adenylate cyclase activators, forskolin and 8-bromo-cAMP, enhanced intercellular connectivity, the number of functional gap junctions, and Cx43 protein expression, whereas the PKA inhibitor, H89, inhibited the stimulatory effect of PGE₂ on gap junctions. These studies suggest that the EP₂ receptor mediates the effects of autocrine PGE₂ on the osteocyte gap junction in response to fluid flow-induced shear stress. These data support the hypothesis that the EP₂ receptor, cAMP, and PKA are critical components of the signaling cascade between mechanical strain and gap junction-mediated communication between osteocytes.

Received for publication, March 24, 2003 , and in revised form, July 30, 2003.

^* This work was supported by an American Federation for Aging Research grant (to J. X. J.), by the Welch Foundation (to J. X. J.), and by National Institutes of Health Grant AR46798 (to J. X. J., E. S., and L. F. B.). 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.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Biochemistry, MSC 7760, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-3796; Fax: 210-567-6595; E-mail: jiangj{at}uthscsa.edu.

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