Osteoclast differentiation factor (ODF), a recently identified cytokine of the TNF family, is expressed as a membrane-associated protein in osteoblasts and stromal cells. ODF stimulates the differentiation of osteoclast precursors into osteoclasts in the presence of M-CSF. Here we investigated the effects of LPS on the gene expression of ODF in mouse osteoblasts and an osteoblast cell line and found that LPS increased the ODF mRNA level. A specific inhibitor of extracellular signal-regulated kinase or protein kinase C inhibited this up-regulation, indicating that extracellular signal-regulated kinase and protein kinase C activation was involved. A protein synthesis inhibitor, cycloheximide, rather enhanced the LPS-mediated increase of ODF mRNA, and both a neutralizing Ab of TNF-α and a specific inhibitor of PGE synthesis failed to block the ODF mRNA increase by native LPS. Thus, LPS directly induced ODF mRNA. Mouse osteoblasts and an osteoblast cell line constitutively expressed Toll-like receptor (TLR) 2 and 4, which are known as putative LPS receptors. ODF mRNA increases in response to synthetic lipid A were defective in primary osteoblasts from C3H/HeJ mice that contain a nonfunctional mutation in the TLR4 gene, suggesting that TLR4 plays an essential role in the process. Altogether, our results indicate that ODF gene expression is directly increased in osteoblasts by LPS treatment via TLR, and this pathway may play an important role in the pathogenesis of LPS-mediated bone disorders, such as periodontitis.

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Variability in speech perception abilities after years of cochlear implant use could reflect differences in central auditory processing of the electrical input provided. Cortical responses were measured in 23 experienced pediatric cochlear implant users who were 12.3+/-3.1 years of age at testing and had used their implants for 6.0+/-2.9 years. All had prelingual onset of deafness. An observer identified blind three types of cortical waveforms ranging from those similar to previous reports to more atypical responses. Children displaying atypical types of responses were implanted at a wide range of ages and had significantly poorer behavioral speech perception scores (P<0.05) than their peers with expected waveforms. Results suggest a persistent immaturity and/or abnormal organization in the auditory cortex in some children.