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.

Macrophage immunomodulation in chronic osteolytic diseases—the case of periodontitis

“…This model allows for investigation of immune events preceding bone loss and their relationship to uncoupling of bone resorption and formation applicable to chronic osteolytic diseases. The relative contribution of innate and adaptive immune cells to onset of bone loss can be dissected through selective cell depletion or alterations of critical functions such as recruitment, reactive oxygen/nitrogen species, and cytokine production . Importantly, ligature experimental PD can be reversed when ligatures are removed after onset of bone loss, allowing for investigation of resolution of periodontal inflammation and bone regeneration, and the testing of therapeutics to enhance the latter .…”

Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis

“…PD, as mentioned previously, is a complex disease with genetic and environmental influences, which can be a challenge to dissect in a clinical setting. Through novel resources and technologies, the mouse has become an invaluable tool to interrogate complex trait diseases, including PD . Herein, through GWAS, we mapped genetic loci in mice that are associated to PD, and one gene family, including the genes Cxcl9 and Cxcl10 , were selected for validation by deleting the CXCR3 receptor.…”

“…The complexity of PD, the heterogeneous genetic composition of patients, and the difficulty to control environmental parameters pose challenges to clinical genetic studies, making animal models an attractive complement to human studies . Indeed, mouse studies on experimental periodontitis induced by Porphyromonas gingivalis ( P. gingivalis ) colonization reveal a strong genetic component in periodontal disease resistance and susceptibility and demonstrate that genetic determinants affect bacterial colonization, as well as periodontal bone levels .…”

The Osteocyte as a Novel Key Player in Understanding Periodontitis Through its Expression of RANKL and Sclerostin: a Review

“…Recent literature has challenged the classical way periodontitis progression is considered, attributing a key role to the osteocyte. Thus far, the emphasis of this inflamed gums disease leading to bone loss has always been on the bacterial pressure activating the inflammatory compartment, which stimulates the activation of osteoclasts that ultimately leads to bone loss [ 1 ••, 2 •]. This review will modify this view by including the recently elucidated role of RANKL and sclerostin expressing osteocytes in the pathogenesis of periodontitis.…”