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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0804314v1 183/5/3390    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Lee, M. S. Articles by Oh, J. PubMed PubMed Citation Articles by Lee, M. S. Articles by Oh, J.

GM-CSF Regulates Fusion of Mononuclear Osteoclasts into Bone-Resorbing Osteoclasts by Activating the Ras/ERK Pathway¹

Myeung Su Lee^*, Hun Soo Kim, Jeong-Tae Yeon, Sik-Won Choi, Churl Hong Chun, Han Bok Kwak^2, and Jaemin Oh^2,

^* Department of Rheumatology, Department of Pathology, Department of Anatomy, and Department of Orthopedic Surgery, School of Medicine, Wonkwang University, Iksan, Jeonbuk, Korea

Osteoclasts are multinucleated cells that are formed by the fusion of mononuclear osteoclasts, which is an essential process in bone resorption leading to bone remodeling. Herein we show that GM-CSF promoted the fusion of prefusion osteoclasts (pOCs). The expression of GM-CSF receptor- was significantly up-regulated at the fusion stage of pOCs induced by RANKL. GM-CSF induced the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which was mediated by inducing NFATc1 via induction of c-Fos. The expression of c-Fos and NFATc1 was regulated by the ERK signaling pathway. Inhibition of ERK and NFATc1 suppressed the expression of DC-STAMP and led to the fusion inhibition of pOC. However, retrovirus-mediated expression of NFATc1 in pOCs rescued the defect in pOC fusion, despite the presence of U0126 and cyclosporin A. GM-CSF-stimulated pOCs had an intact actin ring and could resorb bone. Importantly, pOCs infected with constitutively active MEK adenovirus expressed c-Fos and NFATc1, followed by the binding of NFATc1 to the DC-STAMP promoter, which enables its transcription and expression. Constitutively active MEK-infected pOCs are able to resorb bone by undergoing cell-cell fusion. Taken together, our results demonstrated that GM-CSF induced fusion of pOCs to form multinucleated osteoclasts, making the osteoclast capable of bone resorption.

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 This study was supported by grants of the Korea Health 21 R&D Project (Ministry of Health, Welfare, and Family Affairs, Republic of Korea, A010251).

² Address correspondence and reprint requests to Dr. Han Bok Kwak and Dr. Jaemin Oh, Department of Anatomy, School of Medicine, Wonkwang University, 344-2 Sinyong-dong, Iksan, Jeonbuk 570-749, Korea. E-mail addresses: hbkwak{at}wonkwang.ac.kr and jmoh{at}wonkwang.ac.kr

³ Abbreviations used in this paper: TRAP, tartrate-resistant acid phosphatase; Atp6v0d2, d2 isoform of vacuolar (H⁺) ATPase V₀ domain; BMM, bone marrow-derived macrophages; CA, constitutively active; ChIP, chromatin immunoprecipitation; CSA, cyclosporin A; DC-STAMP, dendritic cell-specific transmembrane protein; DN, dominant-negative; EMSA, electrophoresis mobility shift assay; MOI, multiplicity of infection; OSCAR, osteoclast-associated receptor; pOC, prefusion osteoclast; RANKL, receptor activator of NF-B ligand.

⁴ The online version of this article contains supplemental material.