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J. Biol. Chem., Vol. 280, Issue 6, 4888-4893, February 11, 2005

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Analysis of Distinct Tartrate-resistant Acid Phosphatase Promoter Regions in Transgenic Mice^*

Weihong Pan, Wendy Mathews, J. Michael Donohue, Margaret L. Ramnaraine, Christine Lynch, Daniel J. Selski, Nicole Walsh¶, A. Ian Cassady||, and Denis R. Clohisy**

From the Department of Orthopedic Surgery, University of Minnesota, Minneapolis, Minnesota 55455, ^¶Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and the ^||Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia

The tartrate-resistant acid phosphatase (TRAP) is present in multiple tissues, including kidney, liver, lung, spleen, and bone. Recent study of (TRAP) gene expression has provided evidence for distinct promoters within the (TRAP) gene, suggesting that the gene has alternative, tissue-preferred mRNA transcripts. Examination of endogenous (TRAP) exon 1B and 1C mRNA transcripts revealed tissue-preferred transcript abundance with increased exon 1B transcripts detected in liver and kidney and increased exon 1C transcripts detected in bone and spleen. In this investigation, we have made transgenic mice that express a marker gene driven by two candidate promoters, designated BC and C, within the (TRAP) gene. The BC and C promoters are 2.2 and 1.6 kb, respectively, measured from the translation initiation site. Evaluation of BC transgenic lines demonstrated robust expression in multiple tissues. In contrast, significant transgene expression was not detected in C transgenic lines. Evaluation of transgene mRNAs in BC transgenic lines revealed that virtually all expression was in the form of B transcripts, suggesting that the tissue-preferred pattern of endogenous (TRAP) was not replicated in the BC transgenic line. Likewise, osteoclastogenic cultures from BC, but not C, transgenic bone marrow cells expressed the transgene following receptor activator of NFB ligand/macrophage colony-stimulating factor stimulation. In conclusion, when compared with the 2.2-kb BC portion of the (TRAP) promoter region, the 1.6-kb C portion does not account for significant gene expression in vivo or in vitro; production of the bone- and spleen-preferred (TRAP) C transcript must depend on regulatory elements outside of the 2.2-kb promoter. As the majority of currently investigated transcription factors that influence transcriptional regulation of osteoclast gene expression bind within the 1.6-kb C portion of the (TRAP) promoter, it is likely that transcription binding sites outside of the 2.2-kb region will have profound effects on regulation of the gene in vivo and in vitro.

Received for publication, August 6, 2004 , and in revised form, December 6, 2004.

^* This work was supported by National Institutes of Health Grants CA90434 and AR47302, the Roby C. Thompson Endowment, and the University of Minnesota Cancer Center transgenic mouse core facility. 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 Orthopedic Surgery, 420 Delaware St. MMC 806, University of Minnesota, Minneapolis, MN 55455. Tel.: 612-626-9934; Fax: 612-624-0944; E-mail: clohi001{at}umn.edu.

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