Figure 5. Osteoclast formation adjacent to inflammatory processes is critically dependent on RANKL expression. In an inflammatory process, there are several cells and mechanisms which can theoretically enhance RANKL. One possibility is that RANKL expressed by T-lymphocytes is important for activation of RANK in macrophages/osteoclast progenitor cells (A). Another possibility is that pro-inflammatory cytokines, such as IL-1 and TNF-, stimulate RANKL expression in periosteal osteoblasts (B). In periodontitis, gingival fibroblasts may also be instrumental, since these can release M-CSF, important for expansion of the pool of cells which are macrophages/osteoclast progenitor cells, as well as RANKL-stimulating cytokines such as IL-1, IL-6, and TNF- (C). The gingival fibroblasts express constitutively very small amounts of RANKL, but the expression can be induced by cytolethal distending toxin (cdt) from Actinobacillus actinomycetemcomitans (Aa). Interestingly, gingival fibroblasts constitutively express substantial amounts of the RANKL inhibitor OPG. A fourth possibility in patients with localized aggressive periodontitis is that leukotoxin expressed by Actinobacillus actinomycetemcomitans plays an important role, due to its capacity to release large amounts of IL-1 from macrophages, which then is important to induce RANKL in osteoblasts (D).