Inflammation and uncoupling as mechanisms of periodontal bone loss

Abstract

Periodontal disease is characterized by both inflammation and bone loss. Advances in research in both these areas have led to a new appreciation of not only each field but also the intimate relationship between inflammation and bone loss. This relationship has resulted in a new field of science called osteoimmunology and provides a context for better understanding the pathogenesis of periodontal disease. In this review, we discuss several aspects of the immuno-inflammatory host response that ultimately results in loss of alveolar bone. A proposal is made that periodontal inflammation not only stimulates osteoclastogenesis but also interferes with the uncoupling of bone formation and bone resorption, consistent with a pathologic process. Furthermore, arguments based on experimental animal models suggest a critical role of the spatial and temporal aspects of inflammation in the periodontium. A review of these findings leads to a new paradigm to help explain more fully the impact of inflammation on alveolar bone in periodontal disease so that it includes the effects of inflammation on uncoupling of bone formation from resorption.

Figure 1.

Stimulation of osteoclastogenesis, bone resorption, and coupled bone formation. RANKL, M-CSF, and TNF directly stimulate the formation of osteoclasts, other cytokines or lipid-based mediators such as prostaglandins or leukotrienes indirectly stimulate osteoclastogenesis by effects on RANKL, M-CSF, or TNF-α, and chemokines affect resorption by stimulating recruitment of osteoclast precursors or osteoclast activity. In periodontitis, inflammatory cytokines IL-1, IL-6, IL-7, IL-11, IL-17, TNF-α, LIF, OSM, and RANKL are thought to be primarily produced by leukocytes. Growth factors such as FGF, PDGF, BMP-2, TGF-β, and IGF are released from bone matrix or synthesized locally by various cell types after bone resorption and stimulate proliferation of osteoblast precursors, osteoblast differentiation, or synthesis of bone matrix. Some chemokines, such as CXCL10, CXCL12, CXCL13, and CCL5, may affect bone formation by effects on osteoblast precursors or osteoblasts.

Figure 2.

Migration of an inflammatory front toward alveolar bone stimulates osteoclastogenesis and may contribute to uncoupled bone formation and resorption. (A) In gingivitis, leukocytes in connective tissue are primarily found close to epithelium. (B) If bacteria or their products penetrate further into connective tissue, the inflammatory front moves closer to bone, where mediators produced by inflammatory cells can stimulate osteoclastogenesis and bone resorption. D1, the distance from the inflammatory front to bone in gingivitis. D2, the distance from the inflammatory front to bone in periodontitis. (C) In bone coupling, the amount of new bone produced equals the amount of resorbed bone, so that there is no net bone loss. A deficit in the number of osteoblasts or reduced bone matrix formation per osteoblast leads to a situation where the full amount of bone resorbed is not replaced, and there is incomplete coupling (uncoupling).