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J. Biol. Chem., Vol. 283, Issue 15, 9917-9924, April 11, 2008

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Osteoclast Precursor Interaction with Bone Matrix Induces Osteoclast Formation Directly by an Interleukin-1-mediated Autocrine Mechanism^*

Zhenqiang Yao, Lianping Xing, Chunlin Qin^¶, Edward M. Schwarz, and Brendan F. Boyce¹

From the Department of Pathology and Laboratory Medicine and the Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642 and the ^¶Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M University System Health Science Center, Dallas, Texas 75246

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) mediate bone resorption in a variety of diseases affecting bone. Like TNF, IL-1 is secreted by osteoclast precursors (OCPs), but unlike TNF, it does not induce osteoclast formation directly from OCPs in vitro. TNF induces IL-1 expression and activates c-Fos, a transcription factor required in OCPs for osteoclast formation. Here, we examined whether IL-1 can induce osteoclast formation directly from OCPs overexpressing c-Fos and whether interaction with bone matrix affects OCP cytokine expression. We infected OCPs with c-Fos or green fluorescent protein retrovirus, cultured them with macrophage colony-stimulating factor and IL-1 on bone slices or plastic dishes, and assessed osteoclast and resorption pit formation and expression of IL-1 by OCPs. We used a Transwell assay to determine whether OCPs secrete IL-1 when they interact with bone matrix. IL-1 induced osteoclast formation directly from c-Fos-expressing OCPs on plastic. c-Fos-expressing OCPs formed osteoclasts spontaneously on bone slices without addition of cytokines. OCPs on bone secreted IL-1, which induced osteoclast formation from c-Fos-expressing OCPs in the lower Transwell dishes. The bone matrix proteins dentin sialoprotein and osteopontin, but not transforming growth factor-β, stimulated OCP expression of IL-1 and induced c-Fos-expressing OCP differentiation into osteoclasts. Osteoclasts eroding inflamed joints have higher c-Fos expression compared with osteoclasts inside bone. We conclude that OCPs expressing c-Fos may induce their differentiation directly into osteoclasts by an autocrine mechanism in which they produce IL-1 through interaction with bone matrix. TNF could induce c-Fos expression in OCPs at sites of inflammation in bone to promote this autocrine mechanism and thus amplify bone loss.

Received for publication, August 3, 2007 , and in revised form, February 1, 2008.

^* This work was supported by National Institutes of Health Grants AR43510 (to B. F. B.) and AR48697 (to L. X.). 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 should be addressed: Dept. of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave, P. O. Box 626, Rochester, NY 14642. Tel.: 585-275-5837; Fax: 585-273-3637; E-mail: Brendan_Boyce{at}urmc.rochester.edu.

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