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J. Biol. Chem., Vol. 282, Issue 45, 33086-33097, November 9, 2007

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Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis^*

Xin Li, Hao Liu, Ling Qin, Joseph Tamasi^¶, Marika Bergenstock, Sue Shapses^||, Jean H. M. Feyen^¶, Daniel A. Notterman^**, and Nicola C. Partridge¹

From the Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, the Department of Pediatrics and Core Expression Facility of Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, ^¶Clinical Discovery Technologies, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, the ^||Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey 08901, and the ^**Departments of Pediatrics and Molecular Genetics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901

Parathyroid hormone (PTH) stimulates bone formation when injected daily but causes severe bone loss with continuous infusion. The mechanism of its paradoxical effects is still elusive. In this study, we compared changes in the gene expression profile in bone induced by intermittent or continuous treatment with three different PTH peptides, PTH-(1-34), -(1-31), and -(3-34), in Sprague-Dawley female rats. PTH-(1-34) regulated numerous genes (1,000), but differentially, in both regimes. PTH-(1-31) regulated a similar number of genes in the intermittent regimen but fewer in the continuous regimen, consistent with its less potent catabolic effect. PTH-(3-34) regulated very few genes in both regimes, which suggests the protein kinase C pathway plays a limited role in mediating the dual effects of PTH, whereas the cAMP-dependent protein kinase A pathway appears to predominate. In the intermittent treatment, many genes encoding signaling mediators, transcription factors, cytokines, and proteases/protease inhibitors are regulated rapidly and cyclically with each PTH injection; genes associated with skeletal development show a slowly accruing pattern of expression. With continuous treatment, some genes are regulated from 6 h, and the mRNA levels are sustained with a longer infusion, whereas others show a kinetic decrease and then increase later. Significant up-regulation of genes stimulating osteoclastogenesis in the anabolic regime suggests a provocative and paradoxical theme for the anabolic effect of PTH that a full anabolic response requires a transient up-regulation of genes classically associated with a resorptive response. Ingenuity pathway analysis was performed on the microarray data. A novel signaling network was established that is differentially regulated in the two PTH treatment regimes. Key regulators are suggested to be AREG, CCL2, WNT4, and cAMP-responsive element modulator.

Received for publication, June 25, 2007 , and in revised form, July 26, 2007.

^* This work was supported in part by National Institutes of Health Grant DK48109 (to N. C. P.). 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 Materials, Results and Discussion, Tables 1-8, Fig. 1, and additional references.

¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Ln., Research Tower 561, Piscataway, NJ 08854. Tel.: 732-235-4552; Fax: 732-235-3977; E-mail: partrinc{at}umdnj.edu.

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