IL-1beta mediates MMP secretion and IL-1beta neosynthesis via upregulation of p22(phox) and NOX4 activity in human articular chondrocytes.

OBJECTIVES: Osteoarthritis (OA) is characterized by a progressive alteration of the biochemical properties of the articular cartilage. Inflammation plays a major role in OA, particularly through the cytokine Interleukine-1ß, promoting reactive oxygen species (ROS) generation and matrix metalloproteinases (MMP) synthesis by the chondrocytes, orchestrating matrix proteolysis. NADPH oxidases (NOX) are membrane enzymes dedicated to the production of ROS. Role of oxidative stress is well established in OA; however, contribution of NOX in this process is still poorly documented. In this study, we addressed the role of NOX in primary human articular chondrocytes (HAC) upon inflammatory conditions--namely IL-1ß and OA. DESIGN: HAC were collected from patients undergoing hip surgery. Chondrocytes were treated with IL-1ß and NOX inhibitors Diphenylene Iodonium, GKT136901, Tiron and Heme oxygenase-1 before MMP expression and NOX activity assessment. Finally, NOX4 expression was compared between OA and non OA parts of hip cartilage (n = 14). RESULTS: This study establishes for the first time in human that NOX4 is the main NOX isoform expressed in chondrocytes. We found a significant upregulation of NOX4 mRNA in OA chondrocytes. Expression of NOX4/p22(phox) as well as ROS production is enhanced by IL-1ß. On the other hand, the use of NOX4 inhibitors decreased IL-1ß-induced collagenase synthesis by chondrocytes. Moreover, our study support the existence of a redox dependant loop sustaining pro-catabolic pathways induced by IL-1ß. CONCLUSIONS: This study points out NOX4 as a new putative target in OA and suggests that NOX-targeted therapies could be of interest for the causal treatment of the pathology.

New imaging tools for mouse models of osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease characterized by a disruption of articular joint cartilage homeostasis. Mice are the most commonly used models to study OA. Despite recent reviews, there is still a lack of knowledge about the new development in imaging techniques. Two types of modalities are complementary: those that assess structural changes in joint tissues and those that assess metabolism and disease activity. Micro MRI is the most important imaging tool for OA research. Automated methodologies for assessing periarticular bone morphology with micro-CT have been developed allowing quantitative assessment of tibial surface that may be representative of the whole OA joint changes. Phase-contrast X-ray imaging provides in a single examination a high image precision with good differentiation between all anatomical elements of the knee joint (soft tissue and bone). Positron emission tomography, photoacoustic imaging, and fluorescence reflectance imaging provide molecular and functional data. To conclude, innovative imaging technologies could be an alternative to conventional histology with greater resolution and more efficiency in both morphological analysis and metabolism follow-up. There is a logic of permanent adjustment between innovations, 3R rule, and scientific perspectives. New imaging associated with artificial intelligence may add to human clinical practice allowing not only diagnosis but also prediction of disease progression to personalized medicine.

Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing.

AIMS: Matrix metalloproteinases (MMPs) play a major role in wound healing: they can degrade all components of the extracellular matrix. In diabetic foot ulcers there is an excess of MMPs and a decrease of the tissue inhibitors of MMPs (TIMPs). This imbalance is probably one cause of impaired healing. However, little is known about changes in MMPs during wound healing. METHODS: Sixteen patients with neuropathic diabetic foot ulcers participated. Wound fluid was collected regularly during the 12-week follow-up period, for measurement of MMP-1, MMP-2, MMP-8, MMP-9 and TIMP-1. Results were analysed by the degree of wound healing: good healers (defined by a reduction of at least 82% in initial wound surface at 4 weeks) and poor healers (reduction of less than 82% in wound surface at 4 weeks). RESULTS: In good healers, levels of MMP-8 and -9 secreted by inflammatory cells decreased earlier. The initial levels of MMP-1 were similar in good and poor healers (P = 0.1) but rose significantly at week 2 in good healers (P = 0.039). There was a significant correlation between a high ratio of MMP-1/TIMP-1 and good healing (r = 0.65, P = 0.008). Receiver Operator Curve (ROC) analysis showed that an MMP-1/TIMP-1 ratio of 0.39 best predicted wound healing (sensitivity = 71%, specificity = 87.5%). CONCLUSIONS: A high level of MMP-1 seems essential to wound healing, while an excess of MMP-8 and -9 is deleterious, and could be a target for new topical treatments. The MMP-1/TIMP-1 ratio is a predictor of wound healing in diabetic foot ulcers.

Reactive oxygen species and NADPH oxidase 4 involvement in osteoarthritis.

Osteoarthritis (OA) is a degenerative chronic disease affecting >300,000 million people around the world as of 2016. Symptomatic measures exist, but there are hardly any curative treatments available. Disruption of the cartilage homeostasis in favor of catabolism leads to cartilage destruction. ROS-macromolecular-induced damage is significantly greater in OA cartilage and OA is described as low-grade chronic systemic inflammation. This review aimed to assess the critical role of cartilage ageing and oxidative stress in the OA process, focusing in particular on NADPH oxidase and especially Nox4 involvement. With age, hypertrophic senescent cells with an altered redox cell profile accumulated. Chondrocytes are more sensitive to oxidant-mediators and the serum level of pro-inflammatory mediators increases. Age-related advanced glycation end products impact on extra cellular matrix (ECM) properties leading to the apoptosis of chondrocytes. A focus on NADPH oxidase-mediated-ROS signaling highlighted the very specific Nox4 isoform, which plays a role on the final common pathway targeting chondrocyte cells. IL-1ß-mediated Nox4 stimulation induced an increase in the levels released by the chondrocyte of MMP-1 and MMP-13 proteins, which are involved in ECM degradation. In comparison with the other Nox isoforms, Nox4 remains unusual, since it is constitutively active, does not depend on cytosolic activator proteins and seems to generate H2O2 thanks to the specific conformation of the Nox4 E-loop. Nox4-induced ROS production appears an essential actor in the OA process and it could be relevant to focus on this target in the aim of discovering and developing new therapeutic strategies.

Ratio of triglycerides to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels.

OBJECTIVE: In patients with type 2 diabetes, a normal HDL cholesterol level does not rule out that LDL particles may be small. Although techniques for analyzing LDL subfractions are not likely to be used in clinical practice, a prediction of LDL size based on a regular lipid profile may be useful for assessment of cardiovascular risk. RESEARCH DESIGN AND METHODS: Sixty patients with type 2 diabetes with acceptable glycemic control and an HDL cholesterol level > or = 1 mmol/l were recruited after cessation of lipid-altering treatments. LDL size was determined by 2-20% PAGE; patients having small LDL (n = 30) were compared with those having intermediate or large LDL (n = 30). RESULTS: Clinical characteristics, pharmacological therapies, lifestyle, and prevalence of diabetes-related complications were similar in both patient groups. LDL size correlated negatively with plasma triglycerides (TGs) (R2 = 0.52) and positively with HDL cholesterol (R2 = 0.14). However, an inverse correlation between the TG-to-HDL cholesterol molar ratio and LDL size was even stronger (R2 = 0.59). The ratio was > 1.33 in 90% of the patients with small LDL particles (95% CI 79.3-100) and 16.5% of those with larger LDL particles. A cutoff point of 1.33 for the TG-to-HDL cholesterol ratio distinguishes between patients having small LDL values better than TG cutoff of 1.70 and 1.45 mmol/l. CONCLUSIONS: The TG-to-HDL cholesterol ratio may be related to the processes involved in LDL size pathophysiology and relevant with regard to the risk of clinical vascular disease. It may be suitable for the selection of patients needing an earlier and aggressive treatment of lipid abnormalities.

[Coronary insufficiency in pheochromocytoma]. / L'insuffisance coronarienne des phéochromocytomes

The authors report the case of a 42 year old female with a phaeochromocytoma who, in the course of a hypertensive episode, had ECG changes typical of a myocardial infarction. These changes regressed within a few days. A normal coronary arteriogram confirmed the purely functional nature of this episode of acute myocardial ischaemia. In addition to the case report, the authors discuss the physio-pathological and electrocardiographic features of the coronary insufficiency of phaeochromocytoma, and also the problem of the rapide regression of the changes of infarction on the ECG.

[Kearns-Sayre syndrome: complete auriculoventricular block, torsade de pointes and ventricular fibrillation]. / Syndrome de Kearns-Sayre: bloc auriculo-ventriculaire complet, torsade de pointes et fibrillation ventriculaire.

The authors present the case of a new case of Kearns-Sayre syndrome, with early manifestations (7 months) and dramatic cardiac course. They document the ultimate and often fatal stage of the cardiac disorders of this syndrome, which was usually related to an asystole due to a total atrio-ventricular block and represented in this case by a ventricular hyperexcitability (ventricular tachycardia--"torsade de pointes"--ventricular fibrillation) occurring on an atrio-ventricular block; only one previous, undocumented case was found in the literature. The literature is reviewed in order to analyze the nature and chronology of the heart disorders in the course of the disease, and stress the screening modalities and therapeutic indications (continuous heart stimulation).

Comparison of the new API Candida system to the ID 32C system for identification of clinically important yeast species.

API Candida was evaluated in comparison with the ID 32C system for the identification of 619 yeast isolates. The sensitivity of API Candida for the identification of the 15 species it claims to identify with and without additional tests was 97.4% (593 of 609) and 75.2% (458 of 609), respectively. The API Candida system is easy to use and rapid (result in 18 to 24 h).