Genes Critical for Developing Periodontitis: Lessons from Mouse Models

Abstract

Since the etiology of periodontitis in humans is not fully understood, genetic mouse models may pinpoint indispensable genes for optimal immunological protection of the periodontium against tissue destruction. This review describes the current knowledge of genes that are involved for a proper maintenance of a healthy periodontium in mice. Null mutations of genes required for leukocyte cell-cell recognition and extravasation (e.g., Icam-1, P-selectin, Beta2-integrin/Cd18), for pathogen recognition and killing (e.g., Tlr2, Tlr4, Lamp-2), immune modulatory molecules (e.g., Cxcr2, Ccr4, IL-10, Opg, IL1RA, Tnf-α receptor, IL-17 receptor, Socs3, Foxo1), and proteolytic enzymes (e.g., Mmp8, Plasmin) cause periodontitis, most likely due to an inefficient clearance of bacteria and bacterial products. Several mechanisms resulting in periodontitis can be recognized: (1) inefficient bacterial control by the polymorphonuclear neutrophils (defective migration, killing), (2) inadequate antigen presentation by dendritic cells, or (3) exaggerated production of pro-inflammatory cytokines. In all these cases, the local immune reaction is skewed toward a Th1/Th17 (and insufficient activation of the Th2/Treg) with subsequent osteoclast activation. Finally, genotypes are described that protect the mice from periodontitis: the SCID mouse, and mice lacking Tlr2/Tlr4, the Ccr1/Ccr5, the Tnf-α receptor p55, and Cathepsin K by attenuating the inflammatory reaction and the osteoclastogenic response.

Keywords: bone resorption; chronic periodontitis; immune modulation; knockout mouse; mouse models; osteoclast; periodontitis; transgenic mice.

Figure 1

Introduction into mouse periodontitis. (A) The sequence of events leading to periodontitis. 1. Bacterial pressure (green; red inactivated) colonizing the tooth area (plaque) and present in the space between the tooth surface and the epithelium (sulcus), causes the JEP to thicken and retract. 2. First line of defense such as polymorphonuclear neutrophils (PMNs) are attracted to the infection, extravasate out of blood vessels (bv) into the tissue, and kill bacteria and remove bacterial products. 3. Langerhans cells, special dendritic cells within epithelium (ep), recognize bacterial products, migrate away and elicit a Th1 response that is present during early inflammation, coincidental with inflammatory mediators such as IL1, TNF-α, and IL-6. 4. Gradually, in a sustained inflammation, this shifts toward a Th2 phenotype with more anti-inflammatory mediators. Experimental evidence for this sequence was demonstrated by Araujo-Pires et al. (8), Arizon et al. (17), and Bittner-Eddy et al. (18). 5. Finally, and archetypal for periodontitis, precursor cells of osteoclasts (OCp) migrate to the alveolar bone (AB) and differentiate into bone degrading multinucleated osteoclasts (OC). pdl, periodontal ligament; JEP, junctional epithelium; Ep, epithelium; bv, blood vessel. (B) Schematic drawing of mouse periodontitis with emphasis on the hard tissues. Redrawn from a microCT image taken from the study by Koide et al. (60). Shown are the full first and part of the second of the three mouse molars of a mandible. The distance between the cementum-enamel-junction and the AB crest (δCEJ-AC) is an objective criterion for establishing periodontitis. This distance increases in periodontitis due to the degradation of AB by OC. The imaginary epithelial border—not visible with microCT is indicated with a black line.

Figure 2

Periodontitis caused by malfunctioning diapedesis. Knockout of leukocyte adhesion molecules such as ICAM-1, LFA-1, and P-selectin and mice with defective TNF-α receptor p55 tumor necrosis factor-α receptor (p55TNF-R1), IL-17RA, or CXCR2 mediated attraction of polymorphonuclear neutrophils (PMNs) causes a diminished penetration of PMNs in the infected periodontium, resulting in hampered clearance of periopathogens (green dots). This may lead to an accumulation of Th1/Th17 cells, both in humans and mice. IL-17 and IL-23 activate alveolar bone loss by increasing pro-osteoclastogenesis cytokines IL-1β and RANKL. This sequence of events can be blocked by anti-IL-17 (26).

Figure 3

Periodontitis caused by defective killing of bacteria. Knockout of pattern recognition receptors such as Toll-like receptors, knockout of lysosomal membrane protein LAMP-2, antimicrobial protein lactoferrin, or plasminogen causes defective clearance of bacteria, leading to activation of the Th1 signaling pathway, and initiating chronic inflammation Alternatively, knockout of genes important for the induction of the Th2 reaction and influx of T regulatory cells such as IL-4, CCL2, and CCR4 that modulate the infection, also lead to enhanced inflammation and an endured Th1 presence, such as shown by Araujo-Pires et al. (8). It can be envisaged that bacterial products accumulate due to ineffective clearance.