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Molecular and Cellular Biology, December 2008, p. 7354-7367, Vol. 28, No. 24
0270-7306/08/$08.00+0 doi:10.1128/MCB.00582-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Altered TNSALP Expression and Phosphate Regulation Contribute to Reduced Mineralization in Mice Lacking Androgen Receptor
,
Hong-Yo Kang,1,2
Chih-Rong Shyr,1,3
Chiung-Kuei Huang,1
Meng-Yin Tsai,1,4
Hideo Orimo,5
Pei-Chun Lin,1
Chawnshang Chang,6* and
Ko-En Huang1,4*
Center for Menopause and Reproductive Medicine Research,1 Graduate Institute of Clinical Medical Sciences, Chang Gung University and Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan,2 Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan,3 Department of Obstetrics and Gynecology, Chang Gung University and Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan,4 Division of Molecular Genetics and Nutrition, Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan,5 George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, New York6
Received 10 April 2008/ Returned for modification 8 July 2008/ Accepted 13 September 2008
While androgen receptor (AR)-deficient mice developed osteopenia in endochondral bones due to the high bone turnover with increased bone resorption by osteoclasts, little is known about the mechanism of intramembranous bone loss contributed by AR in osteoblasts. Here, we discovered a dramatic decrease in the area of calcification, new bone, and the number of osteocytes in calvaria from AR-deficient mice related to a reduction in mineralization caused, in part, by the diminished activity of AR-deficient osteoblasts. Enforced AR expression in differentiated osteoblasts boosts mineralization while knockdown of AR expression prevents androgen-induced mineralization. We identified the tissue-nonspecific alkaline phosphatase (TNSALP) and several members of small integrin binding ligand N-linked glycoprotein (SIBLING) gene family as androgen target genes required for AR-mediated bone formation. We show that inorganic phosphate (Pi) levels and TNSALP activity increased in response to androgen/AR and Pi signals increase the expression and translocation of AR. The ectopic expression of TNSALP or Pi partially rescued the bone loss due to AR deficiency. Thus, androgen/AR signaling plays an essential role in bone formation by coordinating the expression of genes associated with phosphate regulation.
* Corresponding author. Mailing address for Ko-En Huang: Center for Menopause and Reproductive Medicine Research, Chang Gung University and Chang Gung Memorial Hospital, 12F, No. 123, Ta Pei Rd., Niao Sung Hsiang, Kaohsiung 833, Taiwan. Phone: (886) 7731-7123, ext. 2000. Fax: (886) 7733-6970. E-mail: khuang{at}adm.cgmh.org. Mailing address for Chawnshang Chang: George Whipple Lab for Cancer Research, Department of Pathology and Urology, University of Rochester Medical Center, 601 Elmwood Ave., Box 626, Rochester, NY 14642. Phone: (585) 275-9994. Fax: (585) 756-4133. E-mail: chang{at}urmc.rochester.edu
Published ahead of print on 6 October 2008.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, December 2008, p. 7354-7367, Vol. 28, No. 24
0270-7306/08/$08.00+0 doi:10.1128/MCB.00582-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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