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J. Biol. Chem., Vol. 278, Issue 45, 44667-44674, November 7, 2003

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Dexamethasone Enhances Osteoclast Formation Synergistically with Transforming Growth Factor- by Stimulating the Priming of Osteoclast Progenitors for Differentiation into Osteoclasts^*

Atsushi Takuma¶, Toshio Kaneda¶||, Takuya Sato, Setsuo Ninomiya, Masayoshi Kumegawa, and Yoshiyuki Hakeda**

From the Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan, Department of Orthopaedic Surgery, Saitama Medical School, Moroyama, Saitama 350-0495, Japan, and ^||Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan

Long-term administration of glucocorticoids (GCs) causes osteoporosis with a rapid and severe bone loss and with a slow and prolonged bone disruption. Although the involvement of GCs in osteoblastic proliferation and differentiation has been studied extensively, their direct action on osteoclasts is still controversial and not conclusive. In this study, we investigated the direct participation of GCs in osteoclastogenesis. Dexamethasone (Dex) at <10^–8 M stimulated, but at >10^–7 M depressed, receptor activator of NF-B ligand (RANKL)-induced osteoclast formation synergistically with transforming growth factor-. The stimulatory action of Dex was restricted to the early phase of osteoclast differentiation and enhanced the priming of osteoclast progenitors (bone marrow-derived monocytes/macrophages) toward differentiation into cells of the osteoclast lineage. The osteoclast differentiation depending on RANKL requires the activation of NF-B and AP-1, and the DNA binding of these transcription factors to their respective consensus cis-elements was enhanced by Dex, consistent with the stimulation of osteoclastogenesis. However, Dex did not affect the RANKL-induced signaling pathways such as the activation of IB kinase followed by NF-B nuclear translocation or the activation of JNK. On the other hand, Dex significantly decreased the endogenous production of interferon-, and this cytokine depressed the RANKL-elicited DNA binding of NF-B and AP-1, as well as osteoclast formation. Thus, the down-regulation of inhibitory cytokines such as interferon- by Dex may allow the osteoclast progenitors to be freed from the suppression of osteoclastogenesis, resulting in an increased number of osteoclasts, as is observed in the early phase of GC-induced osteoporosis.

Received for publication, January 8, 2003 , and in revised form, August 25, 2003.

^* This work was supported by Grant-in-aid for Scientific Research 15591946 from the Japanese Ministry of Education, Science, Sports, and Culture. 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.

^¶ Contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 81-492-79-2769; Fax: 81-492-71-3523; E-mail: y-hakeda{at}dent.meikai.ac.jp.

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