Host-response therapeutics for periodontal diseases

Abstract

Periodontal diseases are initiated by Gram-negative tooth-associated microbial biofilms that elicit a host response, with resultant osseous and soft tissue destruction. In response to endotoxins derived from periodontal pathogens, several osteoclast-related mediators target the destruction of alveolar bone and supporting connective tissues. Major drivers of this aggressive tissue destruction are matrix metalloproteinases (MMPs), cathepsins, and other osteoclast-derived enzymes. This article focuses on the downstream factors of the osteoclast responsible for the degradation of bone and soft tissues around teeth and oral implants. Furthermore, therapeutic approaches that target MMP-2, -8, and -9 inhibition, such as MMP inhibitors, chemically modified tetracyclines, and subantimicrobial formulations of tetracycline analogues, are discussed. The use of rapid, chair-side tests of MMP activity, in particular for MMP-8 and bone collagen fragments, show strong potential as non-invasive measures of tissue health or disease. In addition, studies using other agents for the preservation of bone mass, such as bisphosphonates that inhibit osteoclast recruitment, are highlighted. The application of these bone-preservation strategies to periodontal management and treatment are discussed in the context of high-risk patients susceptible to disease reactivation or disease complications.

Figure 1

Distribution of proteases in the human degradome involved in tumorogenesis, wound repair, and tissue destruction. A gray line indicates each individual enzyme, and those with tumor-protective properties are shown in red. Numbers at the edge represent different protease families of each catalytic class according to MEROP database numbering. Adapted with permission from Macmillian Publishers, copyright 2007.

Figure 2

Schematic overview of the key biomarkers related to periodontal disease progression. Initial events are triggered by LPS from Gram-negative plaque biofilms on the periodontal tissues. As a first line of defense, PMNs are recruited to the site. Monocytes and activated macrophages respond to endotoxin by releasing cytokines (TNF and IL-1) that direct further destruction processes. MMPs, which can act as powerful collagen-destroying enzymes, are produced by fibroblasts and PMNs. TNF, IL-1, and receptor activator of nuclear factor-kappa B ligand (RANKL) are elevated in active sites and mediate osteoclastogenesis and bone breakdown. Bone-specific markers, such as ICTP, are released into the surrounding area and transported by way of gingival crevicular fluid into the sulcus or pocket and serve as potential biomarkers for periodontal disease detection. Adapted with permission from Blackwell Publishing.

Figure 3

Potential therapeutic strategies to treat bone resorption: agents that block the differentiation or activity of osteoclasts are potential therapeutic agents. Osteoprotegerin (OPG) inhibits the differentiation of osteoclasts through its action as a decoy receptor that blocks receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) and RANK juxtacrine interaction. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory molecules (including p38 mitogen-activated protein kinase inhibitors, c-jun N-terminal kinase inhibitors, NF-κB inhibitors, and the specific, high-affinity IL-1 inhibitor IL-1 [TRAP]) can inhibit the formation of hemato-progenitor cells to preosteoclasts. Antibodies to RANKL can also block this interaction. MMP inhibitors reduce the protease degradation of the organic matrix, and anti-integrins block the initial osteoclast adhesion to the matrix. Bisphosphonates and MMP inhibitors work at the site of the osteoclast adhesion zone to the mineralized matrix in blocking bone resorption. M-CSF = macrophage colony-stimulating factor; sRANKL = soluble RANKL; TNFsRC = TNF soluble receptor. Adapted with permission from Blackwell Publishing.

Figure 4

MMP inhibition reduces disease activity in patients with severe periodontitis. Effect of SDD on clinical attachment loss ≥2 mm from baseline to 9 months. Tooth sites were stratified by degree of disease severity, based on PD at baseline. Mean per-patient percentages (± SE) are presented. The more severe the disease state, the greater the observed attenuation of disease activity by SDD therapy. Adapted from reference .

Figure 5

Effect of subantimicrobial-dose doxycycline (SDD) or placebo in combination with surgery on clinical parameters and ICTP for initial pocket ≥7 mm. The bars represent per-patient standard errors. P values indicate significant changes over time within a treatment as determined by the Quade test. Adapted from reference .