Hypercholesterolemia boosts joint destruction in chronic arthritis. An experimental model aggravated by foam macrophage infiltration.

OBJECTIVE: The aim of this study was to determine whether hypercholesterolemia increases articular damage in a rabbit model of chronic arthritis. METHODS: Hypercholesterolemia was induced in 18 rabbits by administrating a high-fat diet (HFD). Fifteen rabbits were fed normal chow as controls. Chronic antigen-induced arthritis (AIA) was induced in half of the HFD and control rabbits, previously immunized, by intra-articular injections of ovalbumin. After sacrifice, lipid and systemic inflammation markers were analyzed in blood serum. Synovium was analyzed by Krenn score, multinucleated cell counting, immunohistochemistry of RAM11 and CD31, and TNF-α and macrophage chemoattractant protein-1 (MCP-1) gene expression. Active bone resorption was assessed by protein expression of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and quantification of cathepsin K, contact surface and the invasive area of pannus into bone. RESULTS: Rabbits receiving the HFD showed higher total serum cholesterol, HDL, triglycerides and CRP levels than rabbits fed a normal diet. Synovitis score was increased in HFD, and particularly in AIA and AIA + HFD groups. AIA + HFD synovium was characterized by a massive infiltration of RAM11+ cells, higher presence of multinucleated foam cells and bigger vascularization than AIA. Cathepsin K+ osteoclasts and the contact surface of bone resorbing pannus were also increased in rabbits with AIA + HFD compared with AIA alone. Synovial TNF-α and MCP-1 gene expression was increased in AIA and HFD rabbits compared with healthy animals. RANKL protein expression in AIA and AIA + HFD groups was higher compared with either HFD or normal groups. CONCLUSIONS: This experimental model demonstrates that hypercholesterolemia increments joint tissue damage in chronic arthritis, with foam macrophages being key players in this process.

Disyuntivas en el tratamiento de la artritis reumatoide: razones para el uso de abatacept / Alternatives in the treatment of rheumatoid arthritis: reasons for using abatacept

La artritis reumatoide (AR) es una enfermedad agresiva y progresiva, cuyo panorama ha cambiado de forma espectacular desde la irrupción de las terapias biológicas a finales de los años noventa. Las principales líneas de actuación en la actualidad se centran en un diagnóstico y tratamiento precoces, lo que ahora es posible gracias a la aparición de nuevos criterios diagnósticos orientados al diagnóstico y clasificación de las formas incipientes e indeterminadas. La instauración del tratamiento de forma precoz, individualizada y agresiva, con unos objetivos concretos de remisión o baja actividad ha mejorado notablemente los resultados conseguidos en muchos pacientes, especialmente en aquellos de peor pronóstico. Abatacept es uno de estos fármacos biotecnológicos que ha entrado a formar parte del arsenal terapéutico de primera línea para el tratamiento de la AR precoz y agresiva. Su eficacia y perfil de seguridad indican que es un fármaco muy prometedor para el tratamiento de los pacientes con AR(AU)

Rheumatoid arthritis (RA) is an aggressive and progressive disease in which the prognosis has improved dramatically since the arrival of biological therapies at the end of the nineties. Nowadays, the main management strategies focus on early diagnosis and treatment, which is now more feasible due to the development of new classification criteria orientated towards diagnosis and classification of early and undifferentiated disease. The implementation of early, individualized and intensive treatment, with the aim of achieving remission or a low disease activity state, has notably improved the results obtained in a great percentage of patients, especially in those with a poorer prognosis. Abatacept is one of the biotechnological agents that have become part of the first line therapeutic armamentarium for early and aggressive RA. The efficacy and safety profile of this drug are very promising for the treatment of patients with RA(AU)

[Alternatives in the treatment of rheumatoid arthritis: reasons for using abatacept]. / Disyuntivas en el tratamiento de la artritis reumatoide: razones para el uso de abatacept.

Rheumatoid arthritis (RA) is an aggressive and progressive disease in which the prognosis has improved dramatically since the arrival of biological therapies at the end of the nineties. Nowadays, the main management strategies focus on early diagnosis and treatment, which is now more feasible due to the development of new classification criteria orientated towards diagnosis and classification of early and undifferentiated disease. The implementation of early, individualized and intensive treatment, with the aim of achieving remission or a low disease activity state, has notably improved the results obtained in a great percentage of patients, especially in those with a poorer prognosis. Abatacept is one of the biotechnological agents that have become part of the first line therapeutic armamentarium for early and aggressive RA. The efficacy and safety profile of this drug are very promising for the treatment of patients with RA.

Inflamación sinovial en un modelo experimental de síndrome metabólico en conejo / Synovial inflammation in an experimental model of metabolic syndrome in the rabbit

Objetivo: Analizar el efecto del síndrome metabólico (SM) sobre la inflamación sinovial en un modelo experimental en conejo. Material y métodos: Se probaron tres intervenciones dietéticas diferentes para inducir un modelo experimental de SM, en 21 conejos New Zealand hembra, de 8 meses de edad: 1) alimentación con dieta enriquecida con 1% de colesterol y 3% de aceite de cacahuete y agua ad libitum; 2) alimentación con dieta normal y agua con 30% de fructosa ad libitum; 3) alimentación con dieta enriquecida con 1% de colesterol y 3% de aceite de cacahuete y agua con 30% de fructosa ad limitum. Los animales se dejaron evolucionar durante 12 semanas y se hizo un seguimiento semanal de peso, glucosa basal, colesterol HDL, triglicéridos. Tras el sacrificio, se tomaron muestras de membrana sinovial para cuantificar el infiltrado macrofágico sinovial mediante inmunohistoquímica. Resultados: La única intervención dietética con la que conseguimos inducir alteraciones asociadas al SM en los conejos fue alimentándolos con una dieta hiperlipémica. Estos animales, además de presentar hiperglucemia y dislipemia, tenían un infiltrado macrofágico sinovial mayor que el del grupo control. Conclusión: La alimentación con dieta hiperlipémica induce alteraciones típicas del SM en el conejo, acompañadas de un aumento del infiltrado macrofágico sinovial, lo que sugiere que el macrófago podría desempeñar un papel importante en el inicio y/o la progresión de la artrosis descrita que se asocia con el SM (AU)

Objetive: To analyze the effect of metabolic syndrome (MS) upon synovial inflammation in an experimental model in the rabbit. Material and methodology: Three different diets were used to induce an experimental model of MS in 21 female New Zealand rabbits (aged 8 months): 1) diet enriched with 1% cholesterol and 3% peanut oil, with water, ad libitum; 2) normal diet, with water, and 30% fructose, ad libitum; 3) diet enriched with 1% cholesterol and 3% peanut oil, with water, and 30% fructose, ad libitum. The animals were followed-up on for 12 weeks, with weekly monitoring of body weight, basal glucose, HDL-cholesterol and triglycerides. Following sacrifice, synovial membrane samples were collected to quantify the synovial macrophage infiltrate using immunohistochemical techniques. Results: The only diet to induce alterations associated with MS in the rabbits was the hyperlipidemic diet. These animals, in addition to presenting hyperglycemia and dyslipidemia, showed greater synovial macrophage infiltration than the control group. Conclusion: A hyperlipidemic diet induces alterations typical of MS in the rabbit, accompanied by an increase in synovial macrophage infiltration (AU)

Pharmacological modulation by celecoxib of cachexia associated with experimental arthritis and atherosclerosis in rabbits.

BACKGROUND AND PURPOSE: Non-steroidal anti-inflammatory drugs improve inflammatory cachexia in several conditions. Thus, we have explored inhibition of cyclooxygenase-2 (COX-2) in an experimental model of rheumatoid cachexia in rabbits. EXPERIMENTAL APPROACH: Chronic arthritis was induced in immunized rabbits by repeated intra-articular injections of ovalbumin. To increase the degree of systemic inflammation and also to induce atherosclerotic lesions, the animals were fed a hyperlipidaemic diet (2% cholesterol and 6% peanut oil) and were given an endothelial injury of the femoral artery. Rabbits were randomized to receive the COX-2 inhibitor celecoxib (10 mg·kg⁻¹ ·day⁻¹) or no treatment. After 4 weeks, sera, peripheral mononuclear cells and vessel specimens were collected. KEY RESULTS: Inhibition of COX-2 by celecoxib modulated the systemic inflammatory response and increased total cholesterol and triglyceride levels. Celecoxib also minimized weight loss and prevented serum albumin fall. At a vascular level, celecoxib reduced COX-2 protein in the femoral arterial wall, but did not modify size or the macrophage infiltration of femoral lesions nor the percentage of rabbits with spontaneous aortic plaques. CONCLUSIONS AND IMPLICATIONS: Our animal model induced a severe inflammatory cachexia, comparable to that of persistently active rheumatoid arthritis. The inhibition of COX-2 by celecoxib improves this state, suggesting that COX products play an important role in its development, without affecting the development or the progression of vascular lesions. Overall, these results suggest that celecoxib might be considered as a new therapeutic tool for the treatment of rheumatoid cachexia.

Improvement of experimental accelerated atherosclerosis by chondroitin sulphate.

The rheumatic diseases have been associated with accelerated atherosclerosis. Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by persistent synovial inflammation which leads to disability and structural changes in joints. Epidemiological studies have demonstrated an increased cardiovascular mortality in patients with RA. In these patients, atherosclerotic plaque occurs earlier, and it has a faster evolution than in general population. Atherosclerosis (AT) is also an inflammatory disease partly mediated by cytokines, many of them involved on chronic synovitis. Our group has developed a rabbit experimental model of AT aggravated by chronic arthritis to study inflammatory mechanisms involved on the progression of vascular lesions and their response to drugs. A preliminary study using this model suggests a beneficial effect of chondroitin sulphate (CS), a drug recommended for the treatment of osteoarthritis, in controlling AT lesions. Yet clinical trials should be conducted with this compound to address the same hypothesis in human studies.

Chondroitin sulfate improves synovitis in rabbits with chronic antigen-induced arthritis.

OBJECTIVE: Our aim was to explore the effect of chondroitin sulfate (CS), a natural glycosaminoglycan with attributed anti-inflammatory properties, on synovitis in a rabbit model of chronic arthritis with intense systemic inflammation bolstered by endothelial lesion and atherosclerotic diet. METHODS: Chronic arthritis was induced by intraarticular injections of ovalbumin in immunized rabbits. Systemic inflammation was boosted in these rabbits by receiving a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. A group of these rabbits were treated with CS (100mg/kg/day). At sacrifice, synovial membranes were isolated, and cyclooxygenase-2 (COX-2) and chemokine (C-C motif) ligand 2 (CCL2) mRNA, as well as protein expression were assayed by quantitative real-time polymerase chain reaction (RT-PCR) and western blot studies. Histological synovial examination was also carried out employing the histopathological synovitis score (Krenn scale). RESULTS: CS diminished both gene expression and protein synthesis of COX-2 and CCL2, and the histopathological score of the synovial membrane, when compared to untreated rabbits. In fact, CS partially prevented the intimal layer proliferation and the inflammatory cell infiltration in the synovial membrane, which was observed in non-treated animals. CONCLUSION: CS reduced the inflammatory response of the synovial membrane, as well as decreased the synovial histopathological lesions in our animal model. Further studies are warranted to demonstrate whether CS might be beneficial in the treatment of inflammatory arthritis.

The 4G/4G PAI-1 genotype is associated with elevated plasma PAI-1 levels regardless of variables of the metabolic syndrome and smoking status. A population-based study in Spanish population.

Reported data about the effect of the 4G/5G PAI-1 polymorphism on plasma PAI-1 levels are controversial. This study was designed to determine the relative effect of the 4G/5G PAI-1 polymorphism on high plasma PAI-1 levels after adjustment for metabolic syndrome - related variables, and to test if this effect is modified by the smoking status. Six hundred and thirty one unrelated subjects (292 men; 35-74 years), from a cross-sectional population-based epidemiological survey in the province of Segovia (Spain) were studied. The higher frequency of high PAI-1 levels was found in 4G/4G subjects (5G/5G 19.4%, 4G/5G 21.6%, 4G/4G 33.7%, p = 0.003). A multiple regression model, adjusted for gender, age, BMI, waist circumference, triglycerides, HDL-cholesterol, HOMA IR and leptin, showed this adjOR: 4G/4G vs 5G/5G: 2.22, p = 0.008. When smoking status - 4G/5G PAI-1 interaction was included as an independent variable these results were not modified. Our results indicate that the 4G/4G PAI-1 genotype might be strongly associated with high PAI-1 levels regardless of metabolic syndrome-related variables and smoking status.