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J. Biol. Chem., Vol. 282, Issue 4, 2346-2354, January 26, 2007

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Attenuation of Bone Mass and Increase of Osteoclast Formation in Decoy Receptor 3 Transgenic Mice^*

Chih-Hsin Tang, Tsui-Ling Hsu^¶, Wan-Wan Lin, Ming-Zong Lai^||, Rong-Sen Yang^**, Shie-Liang Hsieh^¶1, and Wen-Mei Fu²

From the Departments of Pharmacology and ^**Orthopaedics, College of Medicine, National Taiwan University, Taipei 100, the ^¶Department of Microbiology and Immunology, National Yang-Ming University, Taipei 112, the ^||Institute of Molecular Biology, Academia Sinica, Taipei 115, and the Department of Pharmacology, China Medical University, Taichung 404, Taiwan

Decoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT, and TL1A, induces osteoclast formation from monocyte, macrophage, and bone stromal marrow cells. However, the function of DcR3 on bone formation remains largely unknown. To understand the function of DcR3 in bone formation in vivo, transgenic mice overexpressing DcR3 were generated. Bone mineral density (BMD) and bone mineral content (BMC) of total body were significantly lower in DcR3 transgenic mice as compared with wild-type controls. The difference in BMD and BMC between DcR3 transgenic and control mice was confirmed by histomorphometric analysis, which showed a 35.7% decrease in trabecular bone volume in DcR3 transgenic mice in comparison with wild-type controls. The number of osteoclasts increased in DcR3 transgenic mice. In addition, local administration of DcR3 (30 µg/ml, 10 µl, once/day) into the metaphysis of the tibia via the implantation of a needle cannula significantly decreased the BMD, BMC, and bone volume of secondary spongiosa in tibia. Local injection of DcR3 also increased osteoclast numbers around trabecular bone in tibia. Furthermore, coadminstration of soluble tumor necrosis factor receptor inhibitor/Fc chimera (TNFRSF1A) but not osteoprotegerin inhibited the action of DcR3. In addition, in an assay of osteoclast activity on substrate plates, DcR3 significantly increased the resorption activity of mature osteoclasts. Treatment with higher concentrations of DcR3 slightly increased nodule formation and alkaline phosphatase activity of primary cultured osteoblasts. These results indicate that DcR3 may play an important role in osteoporosis or other bone diseases.

Received for publication, March 31, 2006 , and in revised form, September 5, 2006.

^* This work was supported by grants from National Science of Council. 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.

¹ To whom correspondence may be addressed. E-mail: slhsieh{at}ym.edu.tw. ² To whom correspondence may be addressed: Dept. of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei 100, Taiwan. Tel.: 886-2-23123456, Ext. 8319; Fax: 886-2-23417930; E-mail: wenmei{at}ha.mc.ntu.edu.tw.

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