Peroxisome proliferator-activated receptor γ1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1β in articular chondrocytes

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in the regulation of many cellular processes. We and others have previously shown that PPARγ activators display anti-inflammatory and chondroprotective properties in vitro and improve the clinical course and histopathological features in an experimental animal model of osteoarthritis (OA). However, the expression and regulation of PPARγ expression in cartilage are poorly defined. This study was undertaken to investigate the quantitative expression and distribution of PPARγ in normal and OA cartilage and to evaluate the effect of IL-1β, a prominent cytokine in OA, on PPARγ expression in cultured chondrocytes. Immunohistochemical analysis revealed that the levels of PPARγ protein expression were significantly lower in OA cartilage than in normal cartilage. Using real-time RT-PCR, we demonstrated that PPARγ1 mRNA levels were about 10-fold higher than PPARγ2 mRNA levels, and that only PPARγ1 was differentially expressed: its levels in OA cartilage was 2.4-fold lower than in normal cartilage (p < 0.001). IL-1 treatment of OA chondrocytes downregulated PPARγ1 expression in a dose- and time-dependent manner. This effect probably occurred at the transcriptional level, because IL-1 decreases both PPARγ1 mRNA expression and PPARγ1 promoter activity. TNF-α, IL-17, and prostaglandin E2 (PGE2), which are involved in the pathogenesis of OA, also downregulated PPARγ1 expression. Specific inhibitors of the mitogen-activated protein kinases (MAPKs) p38 (SB203580) and c-Jun N-terminal kinase (SP600125), but not of extracellular signal-regulated kinase (PD98059), prevented IL-1-induced downregulation of PPARγ1 expression. Similarly, inhibitors of NF-κB signaling (pyrrolidine dithiocarbamate, MG-132, and SN-50) abolished the suppressive effect of IL-1. Thus, our study demonstrated that PPARγ1 is downregulated in OA cartilage. The pro-inflammatory cytokine IL-1 may be responsible for this downregulation via a mechanism involving activation of the MAPKs (p38 and JNK) and NF-κB signaling pathways. The IL-1-induced downregulation of PPARγ expression might be a new and additional important process by which IL-1 promotes articular inflammation and cartilage degradation

Polymorphisms in RYBP and AOAH Genes Are Associated with Chronic Rhinosinusitis in a Chinese Population: A Replication Study

BACKGROUND: The development of CRS is believed to be the result of combined interactions between the genetic background of the affected subject and environmental factors. OBJECTIVES: To replicate and extend our recent findings from genetic association studies in chronic rhinosinusitis (CRS) performed in a Canadian Caucasian population in a Chinese population. METHODS: In a case-control replication study, DNA samples were obtained from CRS with (n  = 306; CRSwNP) and without (n = 332; CRSsNP) nasal polyps, and controls (n = 315) in a Chinese population. A total of forty-nine single nucleotide polymorphisms (SNPs) selected from previous identified SNPs associated with CRS in Canadian population, and SNPs from the CHB HapMap dataset were individually genotyped. RESULTS: We identified two SNPs respectively in RYBP (rs4532099, p = 2.15E-06, OR = 2.59) and AOAH (rs4504543, p = 0.0001152, OR = 0.58) significantly associated with whole CRS cohort. Subgroup analysis for the presence of nasal polyps (CRSwNP and CRSsNP) displayed significant association in CRSwNP cohorts regarding to one SNP in RYBP (P = 3.24(E)-006, OR = 2.76). Evidence of association in the CRSsNP groups in terms of 2 SNPs (AOAH_rs4504543 and RYBP_rs4532099) was detected as well. Stratifying analysis by gender demonstrated that none of the selected SNPs were associated with CRSwNP as well as CRSsNP. Meanwhile 3 SNPs (IL1A_rs17561, P = 0.005778; IL1A_rs1800587, P = 0.009561; IRAK4_rs4251513, P = 0.03837) were associated with serum total IgE level. CONCLUSIONS: These genes are biologically plausible, with roles in regulation of transcription (RYBP) and inflammatory response (AOAH). The present data suggests the potential common genetic basis in the development of CRS in Chinese and Caucasian population

Eustachian tube symptoms are frequent in chronic rhinosinusitis and respond well to endoscopic sinus surgery

BACKGROUND: Symptoms of Eustachian tube (ET) dysfunction are seldom assessed in patients with chronic rhinosinusitis (CRS). The Sino-Nasal Outcome Test (SNOT-22) quality-of-life tool includes two questions that specifically screen for symptoms of ET dysfunction (Ear Fullness; Ear Pain). OBJECTIVE: The purpose of this study was to determine the extent to which these ET symptoms were present in patients with CRS, and whether these symptoms respond to endoscopic sinus surgery (ESS). METHODOLOGY: SNOT-22 data collected prospectively at time of recruitment into IRB-approved clinical trials or case-control studies in CRS was pooled to provide a cross section of the frequency and severity of ET dysfunction. When applicable to the trials, the SNOT-22 was repeated at least 3 months following ESS. RESULTS: Five trials rendering 131 patients were available for assessment. The control group comprised of 251 participants from two case-control studies. Ear Fullness of equal/greather than 1 was reported in 80/131 CRS patients compared to 45/251 control patients. Ear Pain of equal/greather than 1 was reported in 39/131 CRS patients compared to 33/251 control patients. Following ESS, mean Ear Fullness and Ear Pain scores decreased to 1.17 and 0.73, respectively. CONCLUSION: Symptoms suggestive of ET dysfunction are frequent in CRS, and for most patients the symptoms will decrease post-ESS to a level comparable with a non-CRS population. Patients whose ET symptoms do not respond to ESS may represent a target population for emerging therapeutic options for ET dysfunction

IRAK4 gene polymorphism and odontogenic maxillary sinusitis

Objectives This study aimed to evaluate whether a specific interleukin-1 receptor-associated kinase-4 (IRAK4) gene polymorphism had any influence on the development of changes in maxillary sinus, particularly in the presence of etiological factors of dental origin.Materials and methods The study population included 153 Portuguese Caucasians that were selected from a database of 504 retrospectively analysed computed tomography (CT) scans. A genetic test was performed, and a model was created through logistic analysis and regression coefficients. The statistical methodologies included were the independent Chi test, Fisher's exact test, binary logistic regression and the receiver operating characteristic (ROC) curve.Results The estimated prevalence of IRAK4 gene polymorphism found in a Portuguese Caucasian population was 26.8 % (CI 95 %) [20.1, 34.7 %]. A model to predict the inflammatory response in the maxillary sinus in the presence etiological factors of dental origin was constructed. This model had the following as variables: previously diagnosed sinusitis, sinus pressure symptoms, cortical bone loss observed on CT, positive genetic test result and radiographic examination that revealed the roots of the teeth communication with the maxillary sinus, which are interpreted as risk factors.Conclusions The constructed model should be considered an initial clinical tool. The area under the ROC curve found, AUC=0.91, revealed that the model correctly predicts the outcome in 91.1 % of cases.info:eu-repo/semantics/publishedVersio

Role of Innate Immunity in the Pathogenesis of Chronic Rhinosinusitis: Progress and New Avenues

Chronic rhinosinusitis is a heterogeneous and multifactorial disease with unknown etiology. Aberrant responses to microorganisms have been suggested to play a role in the pathophysiology of the disease. Research has focused on the presence, detection, response to, and eradication of these potential threats. Main topics seem to center on the contribution of structural cells such as epithelium and fibroblasts, on the consequences of activation of pattern-recognition receptors, and on the role of antimicrobial agents. This research should be viewed not only in the light of a comparison between healthy and diseased individuals, but also in a comparison between patients who do or do not respond to treatment. New players that could play a role in the pathophysiology seem to surface at regular intervals, adding to our understanding (and the complexity) of the disease and opening new avenues that may help fight this incapacitating disease

Association between polymorphisms and IgE levels.

<p>BETA: regression coefficient; SE: standard error; R2: regression r-squared; T: Wald test (based on t-distribtion); P: p-value.</p