SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis

Abstract

The host immune response plays a key role in bacteria-induced alveolar bone resorption. Endogenous control of the magnitude and duration of inflammatory signaling is considered an important determinant of the extent of periodontal pathology. Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling pathways and may play a role in restraining periodontal inflammation. We hypothesized that SOCS-3 regulates alveolar bone loss in experimental periodontitis. Periodontal bone loss was induced in 16-wkold myeloid-specific SOCS-3-knockout and wild-type (WT) C57Bl6-B.129 mice by oral inoculation 9 times with 10 9 colony-forming units of Porphyromonas gingivalis A7436 through an oral gavage model for periodontitis. Sham controls for both types of mice received vehicle without bacteria. The mice were euthanized 6 wk after the last oral inoculation. Increased bone loss was demonstrated in P. gingivalis-infected SOCS-3-knockout mice as compared with P. gingivalis-infected WT mice by direct morphologic measurements, micro-computed tomography analyses, and quantitative histology. Loss of SOCS-3 function resulted in an increased number of alveolar bone osteoclasts and increased RANKL expression after P. gingivalis infection. SOCS-3 deficiency in myeloid cells also promotes a higher P. gingivalis lipopolysaccharide-induced inflammatory response with higher secretion of IL-1β, IL-6, and KC (IL-8) by peritoneal macrophages as compared with WT controls. Our data implicate SOCS-3 as a critical negative regulator of alveolar bone loss in periodontitis.

Suppressor of cytokine signaling 1 expression during LPS-induced inflammation and bone loss in rats

“…18,19 Furthermore, a recent report identified SOCS3 as a critical negative regulator of alveolar bone loss in experimental periodontitis induced in SOCS-3-knockout mice. 20 Supporting these findings, our group recently reported that SOCS1 and SOCS3 expression is correlated with the overall severity of inflammation and the expression of proinflammatory cytokines in a rat model of ligature-induced periodontitis. 21 This model is marked by the presence of a plethora of bacterial virulence factors from endogenous bacterial species resulting in periodontal inflammation and bone loss.…”

Genes Critical for Developing Periodontitis: Lessons from Mouse Models

“…Mice with a null-mutation of Socs-3 , the “Suppressor of Cytokine Signaling” (SOCS)-3 proteins, develop periodontitis when they are infected with P. gingivalis . In this specific experimental periodontitis mouse model, the investigators have noted increased expression of RANKL and an increase in osteoclast activity ( 39 ); moreover, in line with the function of Socs-3 , they showed an increased expression of pro-inflammatory cytokines such as IL-1β and IL-6.…”

“…Apparently, analogous to Bert Vogelstein’s famous second hit hypothesis for developing colorectal cancer ( 97 ), where two hits are required to develop disease (colorectal cancer), one could thus postulate that both an underlying genetic defect and a bacterial challenge are required for developing periodontitis. For seven genes: IL17-ra ( 10 ), IL1-ra ( 50 ), Socs-3 ( 39 ), IL-10 as well as its downstream modulator Stat3 ( 55 ) and adhesion molecules Icam-1 ( 11 ) and Beta6 integrin ( 27 ), only the combination of functional loss with bacterial pressure resulted in periodontitis.…”

Capsular‐defective Porphyromonas gingivalis mutant strains induce less alveolar bone resorption than W50 wild‐type strain due to a decreased Th1/Th17 immune response and less osteoclast activity

“…Then, the percentage of alveolar bone loss was calculated using the formula: alveolar bone loss = 1‐(remaining bone volume/VOI) × 100, using an analysis software and considering the VOI as 100%. For SEM analysis, bone loss was quantified at magnification ×30 using a scanning electron microscope, determining the area of bone loss between the mesial surface of M/M1 and the distal surface of D/M3, and between the CEJ and the alveolar bone crest (ABC), as described previously . All data were collected by a single observer (GM) who was masked to conditions of the maxillae samples.…”