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Original Article

Tumor Necrosis Factor Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction

^a Department of Biochemistry, School of Dentistry, Showa University, Tokyo 142-8555, Japan
^b The Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan
^c Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., Tochigi 329-0512, Japan
^d St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia
Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.81-3-3784-555581-3-3784-8162

suda{at}showa-u.ac.jp

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMM) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMM were further cultured for 3 d with mouse tumor necrosis factor (TNF-) in the presence of M-CSF. Osteoclast formation induced by TNF- was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMM prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-. Osteoclasts induced by TNF- formed resorption pits on dentine slices only in the presence of IL-1. These results demonstrate that TNF- stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF- together with IL-1 may play an important role in bone resorption of inflammatory bone diseases.

Key Words: bone resorption • tumor necrosis factor receptor • nuclear factor-B • macrophage colony-stimulating factor • interleukin-1

Abbreviations used in this paper: 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; JNK, c-Jun NH₂-terminal kinase; M-BMM, M-CSF–dependent bone marrow macrophages; M-CSF, macrophage CSF; NF-B, nuclear factor B; OCIF, osteoclastogenesis inhibitory factor; ODF, osteoclast differentiation factor; OPGL, osteoprotegerin ligand; RANKL, receptor activator of NF-B ligand; RT-PCR, reverse-transcriptase PCR; TRAP, tartrate-resistant acid phosphatase.

© 2000 The Rockefeller University Press

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