We hypothesized that the secretion of inflammatory mediators from synoviocytes affects the chondrocyte homeostasis of articular cartilage. This study was a preliminary attempt to elucidate the molecular mechanisms by which soluble mediators obtained from activated synoviocytes induce oxidative stress and inflammation in chondrocytes. We measured the concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), nerve growth factor (NGF), superoxide anion (O 2•− ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO • ) from articular human cells. First, we created a conditional basal medium by exposing synoviocytes (HS) to monosodium urate crystals (CBM). The chondrocytes were exposed to either CBM (CCM), urate crystals directly (CMSU), or remained untreated (CC) as a negative control. Data were analyzed by ANOVA tests; Bonferroni test was performed for multiple comparisons between groups. Interestingly, we observed that mediators of inflammation and oxidative stress were significantly higher in CCM than CMSU and CC groups (P<0.01). The specific concentrations were as follows: 19.85 ng/mL of IL-6, 9.79 ng/mL of IL-8, 5.17 ng/mL of NGF, and 11.91 ng/mL of MCP-1. Of note, we observed the same trend for reactive oxygen and nitrogen species (P<0.001). Soluble mediators secreted by synoviocytes after being activated with MSU crystals (as observed in individuals who present gout attacks) trigger chondrocyte activation intensifying the articular inflammatory, oxidative, and pain states that damage cartilage in OA; this damage is more severe even when compared to HC directly exposed to monosodium urate crystals.

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BackgroundThe hallmark of osteoarthritis (OA) is the breakdown of articular cartilage. Articular cartilage is an avascular tissue, and this generates a hypoxic microenvironment. Hypoxia inducible factor-1α (HIF-1α) is the main transcriptional regulator of cellular and developmental response to hypoxia.ObjectivesThe present study was designed to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA.MethodsA total of 243 unrelated Mexican-mestizo individuals comprising 93 knee OA patients and 150 healthy controls were recruited into the study. 42 genetic polymorphisms from 22 genes involved in the HIF-1α signaling pathway (PIK3R1, AKT2, GSK3B, IL6, AGER, HIF1A, EGLN1, VHL, HIF1AN, VEGFA, EPO, NOS2, NOS3, IGF1, EGF, EDN1, MMP1, MMP3, MMP13, CA, COL2A1, COL3A1) were genotyped in cases and controls using TaqMan-based allelic discrimination assays.ResultsAfter adjusting for age, sex and admixture, significant associations with knee OA were found for 7 SNPs in the case-control study. The following genotypes and alleles were associated with protection against OA: the CT genotype of the HIF1AN rs11190613 polymorphism (OR=0.44, 95% CI=0.19–1.0, P=0.05); the AA genotype of the VEGFA rs1570360 polymorphism (OR=0.14, 95% CI=0.02–0.69, P=0.016); the GT genotype and T allele of the VEGFA rs729761 polymorphism (OR=0.47, 95% CI=0.22–1.0, P=0.05; and OR=0.51, 95% CI=0.27–0.97, P=0.041, respectively); the GA genotype of the COL2A1 rs1793953 polymorphism (OR=0.40, 95% CI=0.20–0.79, P=0.008); and the GG genotype and G allele of the CKM rs4884 polymorphism (OR=0.34, 95% CI=0.14–0.84, P=0.019; and OR=0.51, 95% CI=0.32–0.82, respectively). Otherwise, the CT genotype of the COL3A1 rs2138533 polymorphism (OR=2.89, 95% CI=1.28–6.5, P=0.01); and the GA genotype of the IGF1 rs35767 polymorphism (OR=2.22, 95% CI=1.11–4.43, P=0.024) were associated with an increased risk of OA. However, by using of epistatic interactions between HIF-1α pathway polymorphisms, we found that the gene-gene interaction had a synergistic effect over the estimated OR-values (see table).abORi ORc* P int VEGFA rs1570360 COL3A1 rs2138533 GGCC10.027CT2.894.51TT1.2411.1 COL3A1 rs2138533 IGF1 rs35767  TG10.037A1.493.26 CKM rs4884 COL3A1 rs2138533  AC10.036T1.274.08 COL2A1 rs1793953 HIF1AN rs11190613 AT10.05C0.710.35ORi = initial OR-value; ORc* = combined OR-value obtained by “b” column interaction with “a” column; P int = P-value of the intreraction.ConclusionsIn this study we could observe that the gene-gene interaction of the HIF-1α signaling pathway highly increases the risk of developing OA, with the exception of COL2A1 and HIF1AN interaction which had a protective role against OA. Further studies are needed to validate this results.References Fernández-Torres J, et al. Polymorphic variation of hypoxia inducible factor-1 A (HIF1A) gene might contribute to the development of knee osteoarthritis: a pilot study. BMC Musculoskelet Disord 2015; 16:218.Rodríguez-Fontanela C, et al. Assessment of osteoarthriti...

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Cholesterol overloads not only trigger hepatic damage, but also affect the gallbladder significantly.

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