Tumor necrosis factor-α (TNF-α) is a cytokine produced by monocytes, macrophages, and T cells and is induced by pathogens, endotoxins, or related substances. TNF-α may play a key role in bone metabolism and is important in inflammatory bone diseases such as rheumatoid arthritis. Cells directly involved in osteoclastogenesis include macrophages, which are osteoclast precursor cells, osteoblasts, or stromal cells. These cells express receptor activator of NF-κB ligand (RANKL) to induce osteoclastogenesis, and T cells, which secrete RANKL, promote osteoclastogenesis during inflammation. Elucidating the detailed effects of TNF-α on bone metabolism may enable the identification of therapeutic targets that can efficiently suppress bone destruction in inflammatory bone diseases. TNF-α is considered to act by directly increasing RANK expression in macrophages and by increasing RANKL in stromal cells. Inflammatory cytokines such as interleukin- (IL-) 12, IL-18, and interferon-γ (IFN-γ) strongly inhibit osteoclast formation. IL-12, IL-18, and IFN-γ induce apoptosis in bone marrow cells treated with TNF-α   in vitro, and osteoclastogenesis is inhibited by the interactions of TNF-α-induced Fas and Fas ligand induced by IL-12, IL-18, and IFN-γ. This review describes and discusses the role of cells concerned with osteoclast formation and immunological reactions in TNF-α-mediated osteoclastogenesis in vitro and in vivo.

Orthodontic force induces osteoclastogenesis in vivo. It has recently been reported that administration of an antibody against the macrophage-colony-stimulating factor (M-CSF) receptor c-Fms blocks osteoclastogenesis and bone erosion induced by tumor necrosis factor-alpha (TNF-alpha) administration. This study aimed to examine the effect of an anti-c-Fms antibody on mechanical loading-induced osteoclastogenesis and osteolysis in an orthodontic tooth movement model in mice. Using TNF receptor 1- and 2-deficient mice, we showed that orthodontic tooth movement was mediated by TNF-alpha. We injected anti-c-Fms antibody daily into a local site, for 12 days, during mechanical loading. The anti-c-Fms antibody significantly inhibited orthodontic tooth movement, markedly reduced the number of osteoclasts in vivo, and inhibited TNF-alpha-induced osteoclastogenesis in vitro. These findings suggest that M-CSF plays an important role in mechanical loading-induced osteoclastogenesis and bone resorption during orthodontic tooth movement mediated by TNF-alpha.

Mechanical stress such as orthodontic tooth movement induces osteoclastogenesis. Sometimes, excessive mechanical stress results in root resorption during orthodontic tooth movement. It has been reported that bisphosphonate inhibits osteoclastogenesis. Recently, there have been concerns for orthodontic patients receiving bisphosphonates. Thus, the aim of this study was to investigate the effect of bisphosphonates on orthodontic tooth movement and root resorption in mice. A nickel-titanium (Ni-Ti) closed coil spring delivering a force of 10 g was inserted between the upper anterior alveolar bone and the first molar in 8-week-old male C57BL/6 mice. Bisphosphonate (2 microg/20 microl) was injected daily into a local site adjacent to the upper molar. After 12 days, the distance the tooth had moved was measured. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells was counted as osteoclasts in histological sections. Root resorption was assessed by scanning electron microscopy. The data were analysed with a Student's t-test. The orthodontic appliance increased the number of osteoclasts on the pressure side and mesial movement of the first molar. Bisphosphonates reduced the amount of tooth movement and the number of osteoclasts. In addition, they also reduced root resorption on the pressure side. Bisphosphonates inhibit orthodontic tooth movement and prevent root resorption during orthodontic tooth movement in mice. These results suggest that bisphosphonates might have an inhibiting effect on root resorption during orthodontic tooth movement in humans and that they may interrupt tooth movement in orthodontic patients undergoing treatment, thus altering the outcome of treatment.