Osteolytic diseases, including rheumatoid arthritis, osteomyelitis, and periodontitis, are usually associated with bacterial infections. However, the precise mechanisms by which bacteria induce bone loss still remain unclear. Evidence exists that Tolllike receptor (TLR) signaling regulates both inflammation and bone metabolism and that the receptor activator of NF-B ligand (RANKL) and its receptor RANK are the key regulators for bone remodeling and for the activation of osteoclasts. Here, we investigate the direct effects of the periodontal pathogen Porphyromonas gingivalis on osteoclast differentiation and show that P. gingivalis differentially modulates RANKL-induced osteoclast formation contingent on the state of differentiation of osteoclast precursors. In addition, although an optimal induction of cytokines by P. gingivalis is dependent on TLR2 and TLR4, as well as myeloid differentiation factor 88 and Toll/IL-1R domain-containing adaptor-inducing IFN-, P. gingivalis utilizes TLR2/ myeloid differentiation factor 88 in modulating osteoclast differentiation. P. gingivalis modulates RANKL-induced osteoclast formation by differential induction of NFATc1 and c-Fos. More importantly, RANKL-mediated lineage commitment also has an impact on P. gingivalis-induced cytokine production. RANKL inhibits P. gingivalis-induced cytokine production by down-regulation of TLR/NF-B and upregulation of NFATc1. Our findings reveal novel aspects of the interactions between TLR and RANK signaling and provide a new model for understanding the mechanism underlying the pathogenesis of bacteria-mediated bone loss.Bone is a dynamic organ that constantly undergoes remodeling throughout life. Under normal conditions, bone is periodically resorbed while new bone is formed. Bone maintains its shape and mineralization through a subtle balance of bone formation and bone resorption. In pathogenic bone loss conditions, such as periodontal disease and rheumatoid arthritis, the balance is broken, and bone resorption outweighs bone formation, leading to bone erosion. One of the characteristic findings in these conditions is increased accumulation of osteoclasts at the site of focal erosion (1).Osteoclasts are the sole bone resorbing cells of the body. They are large, multinucleated cells derived from hematopoietic precursor cells of the monocyte-macrophage lineage, the same precursor cells that also give rise to macrophages and dendritic cells (1-4). Osteoclast differentiation is regulated by two essential molecules: the macrophage colony-stimulating factor (M-CSF) 3 and the receptor activator of NF-B ligand (RANKL), a tumor necrosis factor (TNF) family cytokine also known as TNF-related activation-induced cytokine (3, 5). Although M-CSF promotes proliferation and survival of osteoclast progenitors, RANKL prompts the cells to differentiate along the osteoclast lineage (2). RANKL also acts as an activating and survival factor for mature osteoclasts. RANKL exerts its effect on osteoclasts by binding to the receptor RANK expressed on osteoclast prec...