Review of osteoimmunology and the host response in endodontic and periodontal lesions

Abstract

Both lesions of endodontic origin and periodontal diseases involve the host response to bacteria and the formation of osteolytic lesions. Important for both is the upregulation of inflammatory cytokines that initiate and sustain the inflammatory response. Also important are chemokines that induce recruitment of leukocyte subsets and bone-resorptive factors that are largely produced by recruited inflammatory cells. However, there are differences also. Lesions of endodontic origin pose a particular challenge since that bacteria persist in a protected reservoir that is not readily accessible to the immune defenses. Thus, experiments in which the host response is inhibited in endodontic lesions tend to aggravate the formation of osteolytic lesions. In contrast, bacteria that invade the periodontium appear to be less problematic so that blocking arms of the host response tend to reduce the disease process. Interestingly, both lesions of endodontic origin and periodontitis exhibit inflammation that appears to inhibit bone formation. In periodontitis, the spatial location of the inflammation is likely to be important so that a host response that is restricted to a subepithelial space is associated with gingivitis, while a host response closer to bone is linked to bone resorption and periodontitis. However, the persistence of inflammation is also thought to be important in periodontitis since inflammation present during coupled bone formation may limit the capacity to repair the resorbed bone.

Keywords: bacteria; bone; chemokine; cytokine; endodontic lesion; gingivitis; inflammation; periodontitis.

Fig. 1

RANKL/OPG balance is an important factor in regulating bone resorption in periodontal and periapical environments. Osteoclast differentiation and activation are driven by the interaction of RANK (receptor activator of nuclear factor-kB) with its ligand, RANKL. Osteoprotegerin, OPG, is a decoy receptor of RANKL that inhibits RANK-RANKL engagement. In homeostatic conditions (left side), RANKL and OPG levels are thought to be in balance so that there is limited osteoclastogenesis and bone resorption. With an inflammatory stimulus, the RANKL/OPG ratio increases in periodontal and periapical tissues and leads to stimulation of osteoclast activity and pathologic bone resorption.

Fig. 2

Cytokine regulation of matrix degradation and bone resorption in periodontal and periapical environments. The presence of microbial pathogens in periodontal and periapical environments trigger an initial production of proinflammatory cytokines, such as TNF-α and IL1β, which stimulate expression and activation of matrix metalloproteinases (MMPs) that degrade extracellular connective tissue matrix. Cytokines such as TNF-α can stimulate osteoclastogenesis independently while other cytokines stimulate RANKL expression that leads to formation of osteoclasts and osteoclast activity. The combined innate and adaptive immune responses are likely to lead to the high levels of inflammation and bone resorption. These proinflammatory cytokines are thought to generate an amplification loop that contributes to periodontal and periapical lesion progression. Conversely, cytokines produced by Th2 cells and Tregs, such as IL-4 and IL-10 have the opposite effect, in part, through stimulating production of tissue inhibitors of matrix metalloproteinases (TIMPs) and OPG as well as restrain inflammatory cytokine production.

Fig. 3

Spatial relationship between an inflammatory infiltrate and periodontal bone loss. In periodontitis, bacteria attach to the tooth surface and invade the adjacent epithelium and connective tissue. This causes formation of an inflammatory infiltrate indicated by the black arrows. If the inflammatory infiltrate is at a distance from bone (left panel), osteoclastogenesis is not stimulated. However, if the infiltrate moves closer to bone (right panel), osteoclasts are induced and bone resorption occurs.

Fig. 4

The role of coupling in periodontal lesion development. Bone formation occurs after bone resorption so that the two processes are coupled. Thus, the resorption pit is occupied by osteoblasts that form new bone. In a normal healthy individual, the amount of bone formed equals the amount resorbed. In pathologic bone resorption, the amount of bone that forms is less than that resorbed so that there is net bone loss. This may be due to the impact of inflammation on bone formation. Inflammation could potentially interfere with coupling by reducing proliferation of osteoblast precursors, inhibiting differentiation of osteoblasts, decreasing osteoblast numbers by stimulating apoptosis, or by interfering with the production of bone matrix.