Role of Suppressors of Cytokine Signaling 3 in Bone Inflammatory Responses

Suppressor of cytokine signaling 3 (SOCS3) is a potent regulator of cytokine signaling in macrophages and T cells. In recent studies, evidence has been provided for SOCS3 activation in all major bone cells including osteoclasts, chondrocytes, synoviocytes, and osteoblasts. The investigation of SOCS3 function in bone remodeling systems implicates SOCS3 as a key signaling molecule in bone cell-mediated inflammatory responses. Both pro- and anti-inflammatory functions of SOCS3 have been demonstrated in different types of bone cells. This review provides an overview of the important role of SOCS3 in inflammatory responses of various bone cells and in bone inflammatory disorders such as periodontal disease and arthritis. Understanding the roles of SOCS3 in inflammatory diseases of bone and joints such as arthritis, osteomyelitis, and periodontal diseases is critical to revealing insights into signaling pathways that can be manipulated in potential therapeutic approaches

Oral Inflammatory Diseases and Systemic Inflammation: Role of the Macrophage

Inflammation is a complex reaction to injurious agents and includes vascular responses, migration, and activation of leukocytes. Inflammation starts with an acute reaction, which evolves into a chronic phase if allowed to persist unresolved. Acute inflammation is a rapid process characterized by fluid exudation and emigration of leukocytes, primarily neutrophils, whereas chronic inflammation extends over a longer time and is associated with lymphocyte and macrophage infiltration, blood vessel proliferation, and fibrosis. Inflammation is terminated when the invader is eliminated, and the secreted mediators are removed; however, many factors modify the course and morphologic appearance as well as the termination pattern and duration of inflammation. Chronic inflammatory illnesses such as diabetes, arthritis, and heart disease are now seen as problems that might have an impact on the periodontium. Reciprocal effects of periodontal diseases are potential factors modifying severity in the progression of systemic inflammatory diseases. Macrophages are key cells for the inflammatory processes as regulators directing inflammation to chronic pathological changes or resolution with no damage or scar tissue formation. As such, macrophages are involved in a remarkably diverse array of homeostatic processes of vital importance to the host. In addition to their critical role in immunity, macrophages are also widely recognized as ubiquitous mediators of cellular turnover and maintenance of extracellular matrix homeostasis. In this review, our objective is to identify macrophage-mediated events central to the inflammatory basis of chronic diseases, with an emphasis on how control of macrophage function can be used to prevent or treat harmful outcomes linked to uncontrolled inflammation

A critical role for suppressors of cytokine signaling 3 in regulating LPS-induced transcriptional activation of matrix metalloproteinase-13 in osteoblasts

Suppressor of cytokine signaling 3 (SOCS3) is a key regulator of cytokine signaling in macrophages and T cells. Although SOCS3 seems to contribute to the balance between the pro-inflammatory actions of IL-6 family of cytokines and anti-inflammatory signaling of IL-10 by negatively regulating gp130/Jak/Stat3 signal transduction, how and the molecular mechanisms whereby SOCS3 controls the downstream impact of TLR4 are largely unknown and current data are controversial. Furthermore, very little is known regarding SOCS3 function in cells other than myeloid cells and T cells. Our previous study demonstrates that SOCS3 is expressed in osteoblasts and functions as a critical inhibitor of LPS-induced IL-6 expression. However, the function of SOCS3 in osteoblasts remains largely unknown. In the current study, we report for the first time that LPS stimulation of osteoblasts induces the transcriptional activation of matrix metalloproteinase (MMP)-13, a central regulator of bone resorption. Importantly, we demonstrate that SOCS3 overexpression leads to a significant decrease of LPS-induced MMP-13 expression in both primary murine calvariae osteoblasts and a mouse osteoblast-like cell line, MC3T3-E1. Our findings implicate SOCS3 as an important regulatory mediator in bone inflammatory diseases by targeting MMP-13

Investigating the Response of Human Neutrophils to Hydrophilic and Hydrophobic Micro-Rough Titanium Surfaces.

Various treatments have been used to change both the topography and chemistry of titanium surfaces, aiming to enhance tissue response and reduce healing times of endosseous implants. Most studies to date focused on bone healing around dental implants occurring later during the healing cascade. However, the impact of the initial inflammatory response in the surgical wound site on the success and healing time of dental implants is crucial for implant integration and success, yet it is still poorly understood. The purpose of this study was to investigate the effect of titanium surface hydrophilicity on the response of human neutrophils by monitoring oxygen radical production, which was measured as chemiluminescence activity. Materials and Methods: Neutrophils were isolated from human donors' blood buffy coats using the double sucrose gradient method. Neutrophils were exposed to both hydrophilic and hydrophobic titanium surfaces with identical topographies in the presence and absence of human serum. This resulted in six experimental groups including two different implant surfaces, with and without exposure to human serum, and two control groups including an active control with cells alone and a passive control with no cells. Two samples from each group were fixed and analyzed by SEM. Comparisons between surface treatments for differences in chemiluminescence values were performed using analysis of variance ANOVA. Results and Conclusion: In the absence of exposure to serum, there was no significant difference noted between the reaction of neutrophils to hydrophilic and hydrophobic surfaces. However, there was a significant reduction in the mean and active chemiluminescence activity of neutrophils to serum-coated hydrophilic titanium surfaces than to serum-coated hydrophobic titanium surfaces. This suggests that surface hydrophilicity promotes enhanced adsorption of serum proteins, which leads to decreased provocation of initial immune cells and reduction of local oxygen radical production during wound healing. This can help explain the faster osseointegration demonstrated by hydrophilic titanium implants

Surgical Treatment of Induced Peri‐Implantitis in the Micro Pig: Clinical and Histological Analysis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141550/1/jper0984.pd

Subgingival Microbiome and Specialized Pro-Resolving Lipid Mediator Pathway Profiles Are Correlated in Periodontal Inflammation

Failure of resolution pathways in periodontitis is reflected in levels of specialized pro-resolving lipid mediators (SPMs) and SPM pathway markers but their relationship with the subgingival microbiome is unclear. This study aimed to analyze and integrate lipid mediator level, SPM receptor gene expression and subgingival microbiome data in subjects with periodontitis vs. healthy controls. The study included 13 periodontally healthy and 15 periodontitis subjects that were evaluated prior to or after non-surgical periodontal therapy. Samples of gingival tissue and subgingival plaque were collected prior to and 8 weeks after non-surgical treatment; only once in the healthy group. Metabololipidomic analysis was performed to measure levels of SPMs and other relevant lipid mediators in gingiva. qRT-PCR assessed relative gene expression (2-ΔΔCT) of known SPM receptors. 16S rRNA sequencing evaluated the relative abundance of bacterial species in subgingival plaque. Correlations between lipid mediator levels, receptor gene expression and bacterial abundance were analyzed using the Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) and Sparse Partial Least Squares (SPLS) methods. Profiles of lipid mediators, receptor genes and the subgingival microbiome were distinct in the three groups. The strongest correlation existed between lipid mediator profile and subgingival microbiome profile. Multiple lipid mediators and bacterial species were highly correlated (correlation coefficient ≥0.6) in different periodontal conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to healthy controls revealed that one bacterial species, Corynebacterium durum, and five lipid mediators, 5(S)6(R)-DiHETE, 15(S)-HEPE, 7-HDHA, 13-HDHA and 14-HDHA, were identified in both conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to after treatment revealed that one bacterial species, Anaeroglobus geminatus, and four lipid mediators, 5(S)12(S)-DiHETE, RvD1, Maresin 1 and LTB4, were identified in both conditions. Four Selenomonas species were highly correlated with RvD1, RvE3, 5(S)12(S)-DiHETE and proinflammatory mediators in the periodontitis after treatment group. Profiles of lipid mediators, receptor gene and subgingival microbiome are associated with periodontal inflammation and correlated with each other, suggesting inflammation mediated by lipid mediators influences microbial composition in periodontitis. The role of correlated individual lipid mediators and bacterial species in periodontal inflammation have to be further studied

Resolvin E1 Reverses Experimental Periodontitis and Dysbiosis

Periodontitis is a biofilm-induced inflammatory disease characterized by dysbiosis of the commensal periodontal microbiota. It is unclear how natural regulation of inflammation affects the periodontal biofilm. Promoters of active resolution of inflammation including Resolvin E1 (RvE1) effectively treat inflammatory periodontitis in animal models. The goals of this study were 1) to compare periodontal tissue gene expression in different clinical conditions, 2) to determine the impact of local inflammation on the composition of subgingival bacteria, and 3) to understand how inflammation impacts these changes. Two clinically-relevant experiments were performed in rats: prevention and treatment of ligature-induced periodontitis with RvE1 topical treatment. The gingival transcriptome was evaluated by RNA-seq sequencing of mRNA. The composition of the subgingival microbiota was characterized by 16S rDNA sequencing. Periodontitis was assessed by bone morphometric measurements and histomorphometry of block sections. H&E and, tartrate resistant acid phosphatase staining were used to characterize and quantify inflammatory changes. RvE1 treatment prevented bone loss in ligature induced periodontitis. Osteoclast density and inflammatory cell infiltration in the RvE1 groups were lower than those in the placebo group. RvE1 treatment reduced expression of inflammation-related genes returning the expression profile to one more similar to health. Treatment of established periodontitis with RvE1 reversed bone loss, reversed inflammatory gene expression and reduced osteoclast density. Assessment of the rat subgingival microbiota after RvE1 treatment revealed marked changes in both prevention and treatment experiments. The data suggest that modulation of local inflammation has a major role in shaping the composition of the subgingival microbiota