Chronic inflammatory processes close to bone often lead to loss of bone in diseases such as rheumatoid arthritis, periodontitis, loosened joint prosthesis and tooth implants. This is mainly due to local formation of bone resorbing osteoclasts which degrade bone without any subsequent coupling to new bone formation. Crucial for osteoclastogenesis is stimulation of mononuclear osteoclast progenitors by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) which induces their differentiation along the osteoclastic lineage and the fusion to mature, multinucleated osteoclasts. M-CSF and RANKL are produced by osteoblasts/osteocytes and by synovial and periodontal fibroblasts and the expression is regulated by pro- and anti-inflammatory cytokines. These cytokines also regulate osteoclastic differentiation by direct effects on the progenitor cells. In the present overview, we introduce the basic concepts of osteoclast progenitor cell differentiation and summarize the current knowledge on cytokines stimulating and inhibiting osteoclastogenesis by direct and indirect mechanisms.

Periodontitis has been associated with rheumatoid arthritis (RA). In experimental arthritis, concomitant periodontitis caused by oral infection with Porphyromonas gingivalis (P.g.) enhances articular bone loss. The aim of this study was to investigate how lipopolysaccharide (LPS) from P.g. stimulates bone resorption. The effects by LPS P.g. and four other TLR2 ligands on bone resorption, osteoclast formation and gene expression in wild type and Tlr2 deficient mice were assessed in ex vivo cultures of mouse parietal bones and in an in vivo model in which TLR2 agonists were injected s.c. over the skull bones. LPS P.g. stimulated mineral release and matrix degradation in the parietal bone organ cultures by increasing differentiation and formation of mature osteoclasts, a response dependent on increased RANKL. LPS P.g. stimulated RANKL in parietal osteoblasts dependent on the presence of TLR2 and through a MyD88 and NF-κB mediated mechanism. Similarly, the TLR2 agonists HKLM, FSL1, Pam2 and Pam3 stimulated RANKL in osteoblasts and parietal bone resorption. LPS P.g. and Pam2 robustly enhanced osteoclast formation in periosteal/endosteal cell cultures by increasing RANKL. LPS P.g. and Pam2 also upregulated RANKL and osteoclastic genes in vivo, resulting in increased number of periosteal osteoclasts and immense bone loss in wild type mice but not in Tlr2 deficient mice. These data demonstrate that LPS P.g. stimulates periosteal osteoclast formation and bone resorption by stimulating RANKL in osteoblasts via TLR2. This effect might be important for periodontal bone loss and for the enhanced bone loss seen in RA patients with concomitant periodontal disease.

Background: The aim of this study is to characterize and evaluate the host response caused by three different models of experimental periodontitis in mice.Methods: C57BL/6 wild‐type female mice were distributed into six experimental groups and sacrificed at 7, 15, and 30 days after the induction of periodontal disease: 1) group C: no treatment control group; 2) group L: periodontal disease induced by ligature; 3) group G‐Pg: oral gavage with Porphyromonas gingivalis (Pg); 4) group G‐PgFn: oral gavage with Fusobacterium nucleatum + Pg; 5) group I‐Pg: heat‐killed Pg injected into the palatal mucosa between the molars; and 6) group I‐V: phosphate‐buffered saline injected into the palatal mucosa. The samples were used to analyze the immune‐inflammatory process in the gingival tissue via descriptive histologic and real‐time polymerase chain reaction analyses. The alveolar bone loss was evaluated using microcomputed tomography. The data were analyzed using the Kruskal‐Wallis test, followed by a post hoc Dunn test and analysis of variance, followed by a Tukey test using a 5% significance level.Results: Only the ligature model displayed significant alveolar bone loss in the initial period (7 days), which was maintained with time. The group injected with heat‐killed Pg displayed significant alveolar bone loss starting from day 15, which continued to progress with time (P <0.05). A significant increase (P <0.05) in the gene expression of proinflammatory cytokines (interleukin‐6 and ‐1β) and proteins involved in osteoclastogenesis (receptor activator of nuclear factor‐κB ligand and osteoprotegerin) was observed in the ligature group on day 7.Conclusion: The ligature and injection of heat‐killed Pg models were the most representative of periodontal disease in humans, whereas the oral gavage models were not effective at inducing the disease under the experimental conditions.

Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.