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Inflammation-induced Bone Remodeling in Periodontal Disease and the Influence of Post-menopausal Osteoporosis

Department of Oral Cell Biology, Umeå University, Umeå SE-901 87, Sweden; Ulf.Lerner{at}odont.umu.se

View larger version (121K): [in a new window]   Figure 1. Inflammation-induced osteoclast formation. (A) The inflammatory process in the gingiva in periodontitis sites consists of mononuclear leukocytes and a large number of newly formed blood vessels. On the surface of the alveolar bone, several mononucleated bone-resorbing osteoclasts are present. The biopsy is from a mink with severe periodontal disease. (B) The inflammatory process in the pseudomembrane present between the prosthesis and femur consists of an infiltrate of mononuclear leukocytes. On the surface of the bone tissue in the femur from a patient re-operated due to loosening of a hip prosthesis, several osteoclasts and a large number of Howship’s resorption lacunae (dashed arrow) can be observed. The photo is a kind gift from Dr. Christopher Collins, University of Bristol, UK, and is reproduced with his permission. (magnification not defined)

View larger version (91K): [in a new window]   Figure 2. Inflammation induced both osteoclast formation (osteolysis) and new bone formation (sclerosis). (A) On the surface of the femur from a patient with a loosened hip joint prosthesis, not only can osteoclasts (arrowhead) be seen, but also active osteoblasts (solid arrow), producing new wowen bone tissue (dashed line), easily distinguishable from the old lamellar bone (open arrow). The photo is a kind gift from Dr. Christopher Collins, University of Bristol, UK, and is reproduced with his permission. (B) In most patients with inflammation-induced apical periodontitis, a zone with bone loss (osteolytic lesions) is observed adjacent to the apices of the roots of the teeth (solid arrow to the left). In some patients, however, the inflammatory process leads to new bone formation and a sclerotic response (dashed arrows to the right) in the jawbones. (magnification not defined)

View larger version (20K): [in a new window]   Figure 3. Several cytokines and inflammatory mediators have been shown to be able to stimulate osteoclast formation and bone resorption, and have therefore been implicated in the pathogenesis of inflammation-induced bone resorption. Some of the cytokines, the two kinins bradykinin and kallidin, as well as thrombin, are stimulatory, whereas other cytokines are inhibitory. The stimulatory cytokines exert their effects not by affecting the osteoclast progenitor cells directly, but by stimulating the RANKL/OPG ratio in periosteal osteoblasts. The inhibitory cytokines cause their effects either indirectly, by affecting osteoblasts, or, in some cases, directly, by affecting the osteoclast progenitor cells. Chemokines are important for the recruitment of osteoclast progenitor cells to the inflammatory site and also for the fusion of these cells to multi-nucleated osteoclasts.

View larger version (16K): [in a new window]   Figure 4. Osteoclastogenesis can be induced not only by RANKL, but also by TNF-, both members of the TNF ligand superfamily. The prerequisite for TNF--induced osteoclast formation is the presence of permissive amounts of RANKL. The mechanisms involved in the effect of TNF- on osteoclast formation involves enhanced expression of IL-1 in both osteoblasts/stromal cells (A) and in osteoclast progenitor cells (B), as well as increased RANK expression in the osteoclast progenitor cells (B).

View larger version (20K): [in a new window]   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).