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J. Biol. Chem., Vol. 281, Issue 17, 11846-11855, April 28, 2006

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Tumor Necrosis Factor- Increases Circulating Osteoclast Precursor Numbers by Promoting Their Proliferation and Differentiation in the Bone Marrow through Up-regulation of c-Fms Expression^*

Zhenqiang Yao¹, Ping Li¹, Qian Zhang, Edward M. Schwarz, Peter Keng^¶, Arnaldo Arbini, Brendan F. Boyce, and Lianping Xing²

From the Department of Pathology and the Department of Orthopedics, ^¶Cancer Research Center, University of Rochester Medical Center, Rochester, New York 14642

Osteoclasts are essential cells for bone erosion in inflammatory arthritis and are derived from cells in the myeloid lineage. Recently, we reported that tumor necrosis factor- (TNF) increases the blood osteoclast precursor (OCP) numbers in arthritic patients and animals, which are reduced by anti-TNF therapy, implying that circulating OCPs may have an important role in the pathogenesis of erosive arthritis. The aim of this study is to investigate the mechanism by which TNF induces this increase in OCP frequency. We found that TNF stimulated cell division and conversion of CD11b⁺/Gr-1^-/lo/c-Fms^- to CD11b⁺/Gr-1^-/lo/c-Fms⁺ cells, which was not blocked by neutralizing macrophage colony-stimulating factor (M-CSF) antibody. Ex vivo analysis of monocytes demonstrated the following: (i) blood CD11b⁺/Gr-1^-/lo but not CD11b^-/Gr-1^- cells give rise to osteoclasts when they were cultured with receptor activator NF-B ligand and M-CSF; and (ii) TNF-transgenic mice have a significant increase in blood CD11b⁺/Gr-1^-/lo cells and bone marrow proliferating CD11b⁺/Gr-1^-/lo cells. Administration of TNF to wild type mice induced bone marrow CD11b⁺/Gr-1^-/lo cell proliferation, which was associated with an increase in CD11b⁺/Gr-1^-/lo OCPs in the circulation. Thus, TNF directly stimulates bone marrow OCP genesis by enhancing c-Fms expression. This results in progenitor cell proliferation and differentiation in response to M-CSF, leading to an enlargement of the marrow OCP pool. Increased marrow OCPs subsequently egress to the circulation, forming a basis for elevated OCP frequency. Therefore, the first step of TNF-induced osteoclastogenesis is at the level of OCP genesis in the bone marrow, which represents another layer of regulation to control erosive disease.

Received for publication, November 28, 2005

^* This work was supported by National Institutes of Health Grants AR48697 (to L. X.) and AR43510 (to B. F. B.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, 601 Elmwood Ave., Box 626, Rochester, NY 14642. Tel.: 585-273-4090; Fax: 585-756-4468; E-mail: Lianping_xing{at}urmc.rochester.edu.

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