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

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stim ulates the differentiation of osteoclast progenitors-of the monocyte/macrop hage lineage into osteoclasts in the presence of macrophage colony-stimulat ing factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cu ltured with M-CSF, M-CSF-dependent bone marrow macrophages (M-BMM phi) appe ared within 3 d. Tartrate-resistant acid phosphatase-positive osteoclasts w ere also formed when M-BMM phi were further cultured for 3 d with mouse tum or necrosis factor alpha (TNF-alpha) in the presence of M-CSF. Osteoclast f ormation induced by TNF-alpha was inhibited by the addition of respective a ntibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastoge nesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RAN KL), nor the Fab fragment of anti-RANK (ODF/RANKL receptor) antibody. Exper iments using M-BMM phi prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced si,signals were important for osteoclast formation induced by TNF-alpha. Osteoclasts induced by TNF-alpha formed re sorption pits on dentine slices only in the presence of IL-1 alpha. These r esults demonstrate that TNF-alpha stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL-RANK system. TNF-cr together with IL-1 alpha may play an important role in bone resorption of inflammatory bone diseases.