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This version published online on March 15, 2007
Endocrinology, doi:10.1210/en.2007-0215
A more recent version of this article appeared on June 1, 2007
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Submitted on February 14, 2007
Accepted on March 5, 2007

Overexpression of {gamma}-glutamyltransferase in transgenic mice accelerates bone resorption and causes osteoporosis

Kiyoshi Hiramatsu, Yutaro Asaba, Sunao Takeshita, Yuji Nimura, Sawako Tatsumi, Nobuyoshi Katagiri, Shumpei Niida, Toshihiro Nakajima, Sakae Tanaka, Masako Ito, Gerard Karsenty, and Kyoji Ikeda*

Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Obu, Aichi 474-8522, Japan; Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550 Japan; National Institute of Biomedical Innovation (NIBIO), Osaka 567-0085, Japan; Department of Genome Science, Institute of Medical Science, St. Marianna University of Medicine, Kanagawa 216-8512, Japan; Department of Orthopedic Surgery, University of Tokyo School of Medicine, Tokyo 113-8655, Japan; Department of Radiology, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan; Department of Genetics and Development, Columbia University, New York, NY 10032, USA

* To whom correspondence should be addressed. E-mail: kikeda{at}nils.go.jp.

We previously identified {gamma}-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. In order to examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages (BMMs) to RANKL, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased RANKL expression in marrow stromal cells, and also stimulated osteoclastogenesis from BMMs at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction, and provides a new target for therapeutic intervention.
Key words: osteoclast • bone resorption • osteoporosis




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