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J. Biol. Chem., Vol. 280, Issue 5, 3974-3981, February 4, 2005

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Amphiregulin Is a Novel Growth Factor Involved in Normal Bone Development and in the Cellular Response to Parathyroid Hormone Stimulation^*

Ling Qin, Joseph Tamasi, Liza Raggatt, Xin Li, Jean H. M. Feyen, David C. Lee¶, Emanuel DiCicco-Bloom||, and Nicola C. Partridge**

From the Physiology and Biophysics and ^||Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, New Jersey 08534, and the ^¶Department of Biochemistry and Biophysics and University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599

Parathyroid hormone (PTH) is the major mediator of calcium homeostasis and bone remodeling and is now known to be an effective drug for osteoporosis treatment. Yet the mechanisms responsible for its functions in bone are largely unknown. Here we report that the expression of amphiregulin (AR), a member of the epidermal growth factor (EGF) family, is rapidly and highly up-regulated by PTH in several osteoblastic cell lines and bone tissues. Other osteotropic hormones (1,25-dihydroxyvitamin D₃ and prostaglandin E₂) also strongly stimulate AR expression. We found all EGF-like ligands and their receptors are expressed in osteoblasts, but AR is the only member that is highly regulated by PTH. Functional studies demonstrated that although AR is a potent growth factor for preosteoblasts, it completely inhibits further differentiation. AR also strongly and quickly stimulated Akt and ERK phosphorylation and c-fos and c-jun expression in an EGF receptor-dependent manner. Moreover, AR null mice displayed significantly less tibial trabecular bone than wild-type mice. Taken together, we have identified a novel growth factor that is PTH-regulated and appears to have an important role in bone metabolism.

Received for publication, August 26, 2004 , and in revised form, October 20, 2004.

^* This work was supported by National Institutes of Health Grants DK48109 (to N. C. P.) and CA43793 (to D. C. L.). 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 a supplemental table and a figure.

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

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