Abstract
Lipoproteins are important bacterial immunostimulating molecules capable of inducing receptor activator of nuclear factor-κB (RANKL) and osteoclast formation in vitro and in vivo . Although these molecules are present in periodontopathogenic bacteria, their role in periodontitis is not known. In this study, we used Pam2CSK4 (PAM2), a synthetic molecule that mimics bacterial lipoprotein, to investigate the effects of lipoproteins on periodontitis in mice. C57BL/6 male mice were randomly divided into three experimental groups: 1) Negative control group: animals received vehicle injection; 2) Positive control group: animals received injection of Escherichia coli lipopolysaccharide (LPS); 3) PAM2 group: animals received PAM2 injection. All the injections were performed bilaterally every other day into the palatal mucosa between first and second molars. After twenty-four days, the animals were euthanized to assess alveolar bone volume (micro-CT), cellular and extracellular composition in the gingiva (stereometric analysis), and osteoclast numbers (TRAP staining). Treatment with either PAM2 or LPS induced gingival inflammation, as demonstrated by increased infiltration of inflammatory cells and enhanced angiogenesis, associated with a smaller number of fibroblasts and decreased extracellular matrix. Importantly, treatment not only with LPS but also with PAM2 resulted in a larger number of TRAP+ multinucleated osteoclasts and significant loss of alveolar bone. Collectively, our data demonstrate that PAM2 can induce gingival inflammation and bone loss in mice, broadening the avenues of investigation into the role of lipoproteins in the pathogenesis of periodontal disease.
Highlights
Periodontitis is a polymicrobial disease characterized by the host inflammation-dependent destruction of periodontal structures, leading to long-term alveolar bone loss and loosening of teeth.[1]
The host response is initiated by the recognition of pathogen-associated molecular patterns (PAMPs), such as the lipoproteins and lipopolysaccharides (LPS) present in Gram-negative bacteria.[2, 3]
Recent findings in mouse models point out the possible transfer of a dysbiotic oral microbiome across individuals and generations, thereby highlighting the importance of identifying bacterial signatures and host receptors that could contribute to the pathogenesis of periodontitis.[8]
Summary
Periodontitis is a polymicrobial disease characterized by the host inflammation-dependent destruction of periodontal structures, leading to long-term alveolar bone loss and loosening of teeth.[1]. Its ubiquitous presence in Gram-negative bacteria makes LPS the most widely studied PAMP, and several studies show the importance of LPS-induced activation of TLR4 for periodontal breakdown.[9,12,20] Many bacteria contain lipoproteins as important virulence factors, caused by their strong immunostimulatory activity.[21] Porphyromonas gingivalis (P. gingivalis) is recognized as an important pathogenic bacterium in human periodontitis These bacteria induce gingival inflammation and periodontal breakdown by activation of TLR2 in experimental models of periodontitis in mice.[22] the bacterial components isolated from P. gingivalis are not the ideal tools to study TLR2-dependent periodontitis, since P. gingivalis LPS may present large variations among companies and batches, because this bacteria is able to modify its PAMPs in order to escape the immune system.[1,23,24]. The mechanisms by which PAM2 induces osteoclastogenesis involve both direct stimulation of osteoclast precursors and product[22,26] In an effort to understand how TLR2 induces periodontitis, the authors compared the effect of PAM2 with that of a well-characterized Escherichia coli LPS.[9,10,12]
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