Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction

Kanichiro Kobayashi, Naoyuki Takahashi, Eijiro Jimi, Nobuyuki Udagawa, Masamichi Takami, Shigeru Kotake, Nobuaki Nakagawa, Masahiko Kinosaki, Kyoji Yamaguchi, Nobuyuki Shima, Hisataka Yasuda, Tomonori Morinaga, Kanji Higashio, T. John Martin, Tatsuo Suda

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1102 Citations (Scopus)


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- BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase-positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor et (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α 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-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL-RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.

Original languageEnglish
Pages (from-to)275-285
Number of pages11
JournalJournal of Experimental Medicine
Issue number2
Publication statusPublished - Jan 17 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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