Adipose tissue: a regulator of inflammation

Adipose tissue is a highly active organ. In addition to storing calories as triglycerides, it also secretes a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. Intriguingly, many, if not most, of these adipose-derived proteins have dual actions; cytokines have both immunomodulatory functions and act as systemic or auto-/paracrine regulators of metabolism, while proteins such as leptin and adiponectin are regulators of both metabolism and inflammation. The production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications.     

软骨下骨成骨细胞在骨性关节炎中的作用与机制

骨性关节炎是一种骨组织代谢疾病,软骨下骨成骨细胞直接参与骨性关节炎的病理过程。成骨细胞表达异常的生物学表型与软骨下骨结构和功能改变密切相关,其可使软骨承受更高的应力;软骨下骨成骨细胞产生的代谢调节因子通过骨和软骨间微结构直接促进软骨细胞退变。免疫和脂类代谢通过成骨细胞调节骨组织代谢,参与骨性关节炎病变过程。进一步阐明软骨下骨成骨细胞在骨性关节炎病变过程中的作用和机制,可为骨性关节炎研究和治疗提供新方法和思路。     

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by a symmetrical, inflammatory arthropathy that frequently results in damage to synovial-lined joints with consequent pain, stiffness, and reduced functional capacity. The prevalence of RA is 0.8–1% in Western Europe and North America, and it is believed to arise from an interplay between genetics and the environment. Smoking is known to be a major risk factor particularly for anticitrullinated protein antibody-positive RA (1), whereas consumption of alcohol reduces both the risk and the severity of RA (2). The severity of RA varies from a mild condition with little joint damage to an unremitting condition that leads to extensive bone and cartilage damage. The radiological severity of damage to the hands and feet is widely used to measure outcome of RA and has been shown to have a significant genetic component (3, 4). Loci genetically associated with radiological damage include DRB1 (5), CD40 (6) and TRAF1/C5 (7), IL-4 (8), and IL-15 (9).A genome-wide association study involving 12,277 RA cases and 28,975 controls, all of European descent, reported association of rs26232 in the first intron of chromosome 5 open reading frame 30 (C5orf30) with risk of RA (10). Importantly linkage disequilibrium did not extend to genes in the flanking regions, indicating that the association was arising from C5orf30. This association was subsequently replicated in a British study of 6,108 RA cases and 13,009 controls (11). In a study of three large European RA populations (n = 1,884), we reported an allele dose association of rs26232 with radiological damage (12).The biological activities of human C5orf30 are unknown, and the precise roles it plays in RA have not yet been reported. There is indirect evidence linking human C5orf30 with immune function via its association with intracellular UNC119 (13); the latter increasing both T-cell activation by up-regulating Lck/Fyn activity and Src kinases regulating macrophages activation (14, 15). There are, however, no studies of the biological functions of human C5orf30 and, in view of the genetic association with RA susceptibility and severity, we have undertaken in silico analysis and both in vitro and in vivo experiments to determine its functional activities in RA. Here, we report C5orf30 to be a yet unidentified negative regulator of tissue damage in RA, acting by modulating the autoaggressive phenotype that is characteristic of RA synovial fibroblasts (RASF). It is highly expressed in the synovium of RA patients compared with healthy and osteoarthritis (OA) predominately by RASF in the lining and sublining layer. These cells play an important role in the initiation and perpetuation of RA and are implicated in cartilage destruction (16). Targeting C5orf30 expression by using siRNA technology resulted in increased invasiveness, proliferation and migration of RASFs in vitro, and modulated expression of genes in RA-relevant pathways including migration and adhesion. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis (CIA) model mice markedly accentuated joint inflammation and cartilage destruction. These data confirm C5orf30 as a previously unidentified regulator of tissue destruction in RA.     

Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals

Summary High plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity, and both PAI-1 and obesity are risk factors for cardiovascular disease. To study the mechanisms underlying increased PAI-1 levels in obese individuals, gene expression and secretion of PAI-1 were measured in human abdominal subcutaneous adipose tissue. A total of 32 obese, otherwise healthy subjects and 10 never-obese healthy subjects with a body mass index (BMI) of 42.6 ± 1.2 and 24.3 ± 1.9 kg/m² (mean ± SEM), respectively, were investigated. Plasma PAI-1 activity, adipose tissue PAI-1 secretion and adipocyte PAI-1 mRNA levels were increased sevenfold (p < 0.0001), sixfold (p < 0.0001) and twofold (p < 0.05), respectively, in the obese group. There were clear associations between adipose tissue secretion of PAI-1 and PAI-1 mRNA levels on the one hand and fat cell volume on the other (r = 0.68, p < 0.0001 and r = 0.51, p < 0.01, respectively, in the obese group). PAI-1 mRNA levels were also related to the amount of PAI-1 secreted among obese individuals (r = 0.31, p = 0.09). It is concluded that adipose tissue secretes significant amounts of PAI-1, that PAI-1 secretion from adipose tissue is increased in obesity, and that PAI-1 secretion is related to the lipid content and cell volume of fat cells. Plasma PAI-1 activity is elevated in obesity, at least in part due to increased gene expression in adipocytes, which, in turn, enhances PAI-1 secretion from adipose tissue. [Diabetologia (1998) 41: 65–71] Received: 26 May 1997 and in revised form: 12 August 1997     

Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein (MOG_35–55)-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNFα, IL-6, IFN-γ, IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1α/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-β) in the spinal cord. Moreover, the abundance of CD4⁺CD25⁺FoxP3⁺ Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-β secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation.     

Perforin is a critical physiologic regulator of T-cell activation

Individuals with impaired perforin-dependent cytotoxic function (Ctx(-)) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). It has been hypothesized that immune hyperactivation during HLH is caused by heightened infection, defective apoptosis/responsiveness of Ctx(-) lymphocytes, or enhanced antigen presentation. Whereas clinical and experimental data suggest that increased T-cell activation drives HLH, potential abnormalities of T-cell activation have not been well characterized in Ctx(-) hosts. To define such abnormalities and to test these hypotheses, we assessed in vivo T-cell activation kinetics and viral loads after lymphocytic choriomeningitis virus (LCMV) infection of Ctx(-) mice. We found that increased T-cell activation occurred early during infection of Ctx(-) mice, while they had viral burdens that were identical to those of WT animals, demonstrating that T-cell hyperactivation was independent of viral load. Furthermore, cell transfer and signaling studies indicated that increased antigenic stimulation, not a cell-intrinsic defect of responsiveness, underlay heightened T-cell activation in vivo. Finally, direct measurement of viral antigen presentation demonstrated an increase in Ctx(-) mice that was proportional to abnormal T-cell activation. We conclude that perforin-dependent cytotoxicity has an immunoregulatory role that is distinguishable from its pathogen clearance function and limits T-cell activation in the physiologic context by suppressing antigen presentation.     

The association between systemic sclerosis and bone mineral density‐ a meta‐analysis of observational studies

Previous research has shown inconsistent effect of systemic sclerosis (SSc) on bone mineral density (BMD). The objective of this study was to perform a meta‐analysis of previous articles to investigate the differences in BMD (g/cm²) between SSc and non‐SSc populations and to discuss potential underlying mechanisms. Twelve full‐text articles (including an outlier study and two studies with identical data) with 662 SSc patients and 886 controls were identified by searching Medline prior to 10 September, 2013 using search terms ‘Systemic sclerosis’ OR ‘scleroderma’ and ‘osteoporosis’ OR ‘bone density’ OR ‘bone mass’. BMD (mean and standard deviation), T‐scores and Z‐scores at lumbar spine, femoral neck and total hip measured by dual‐energy X‐ray absorptiometry were extracted. Meta‐analysis showed that a lower level of BMD was found in SSc patients, with weighted mean difference of ?0.343 (95% CI: ?0.500 to ?0.186) at femoral neck, ?0.084 (95% CI: ?0.110 to ?0.057) at total hip and ?0.104 (95% CI: ?0.135 to ?0.073) at the lumbar spine. We conclude that patients with SSc may have a lower BMD level than healthy controls.     

Anemia is Associated with Bone Mineral Density in Chronic Obstructive Pulmonary Disease

Abstract

Objective: Patients with chronic obstructive pulmonary disease (COPD) often suffer from systemic co-morbidities, including anemia. However, anemia is related to multiple outcomes in COPD and in other chronic diseases, but it's impact is underestimated in COPD. The objective of the present study was to relate anemia in patients with COPD with disease-related outcomes, systemic inflammation and COPD related co-morbidities. Methods: Data of 321 patients with COPD admitted for pulmonary rehabilitation were analysed. Besides general characteristics, lung function, body composition, arterial gases and plasma haemoglobin concentration, disease-related outcomes (health-related quality of life by St. George's Respiratory Questionnaire, 6-minute walking distance, mMRC dyspnea scale, and BODE index), systemic inflammation (C-reactive protein (CRP)) and self-reported and objectified co-morbidities (low muscle mass, osteoporosis, renal failure, risk for undernutrition) were taken into account. Results: First, 20% of the patients were anemic, and 8% was polycythemic. Polycythemic patients had a lower proportion of men and a lower proportion of low muscle mass compared to the other groups. Anemic patients had higher plasma CRP levels and lower total body bone mineral density compared to the other groups. There was no difference in disease-related outcomes or other co-morbidities in the patients with and without anemia. Even after adjustment for confounders, anemia was an independent determinant for higher CRP levels and lower bone mineral density. Conclusion: Anemia is frequently present in patients with COPD and there is evidence that it is associated with lower whole body bone mineral density.     

Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives

Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Despite many undeniable therapeutic successes obtained, breast cancer still remains, however, a major health issue. In the last few years, thanks to aromatase inhibitors, the hormone therapy for oestrogen-dependent breast cancer has evolved in terms of efficacy and tolerability; at the same time, it has enabled us to better define the role of oestrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. A more recent hypothesis suggests that adipocytes and their autocrine (paracrine and endocrine actions) are at the centre of such an etiopathogenetic mechanism. A better understanding of the main mechanisms that link together menopause, body-weight increase and hormone-dependent breast cancer is paramount to enable the identification of key molecules involved in the development of breast carcinoma and suggest new therapeutic options. The present review will discuss important findings on the therapeutic aspects of adipose tissue and adipokines as a target for treatment of hormone-dependent breast cancer.     

PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte contractility

PICOT (PKC-interacting cousin of thioredoxin) was previously shown to inhibit the development of cardiac hypertrophy, concomitant with an increase in cardiomyocyte contractility. To explore the physiological function of PICOT in the hearts, we generated a PICOT-deficient mouse line by using a gene trap approach. PICOT^−/− mice were embryonic lethal indicating that PICOT plays an essential role during embryogenesis, whereas PICOT^+/− mice were viable with no apparent morphological defects. The PICOT protein levels were reduced by about 50% in the hearts of PICOT^+/− mice. Significantly exacerbated cardiac hypertrophy was induced by pressure overload in PICOT^+/− mice relative to that seen in wild type littermates. In line with this observation, calcineurin-NFAT signaling was greatly enhanced by pressure overload in the hearts of PICOT^+/− mice. Cardiomyocytes from PICOT^+/− mice exhibited significantly reduced contractility, which may be due in part to hypophosphorylation of phospholamban and reduced SERCA activity. These data indicate that the precise PICOT protein level significantly affects the process of cardiac hypertrophy and cardiomyocyte contractility. We suggest that PICOT plays as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator.     

The treatment of oesophageal varices: a debate and a discussion

At the Biennial Meeting of the International Association for the Study of the Liver, in Cape Town, South Africa, 20–24 February 1996, the treatment of oesophageal varices was selected as a subject for the discussion of controversies in portal hypertension. This review gives a summary of that discussion. Dr Didier LeBrec gave a broad overview of the medical management of oesophageal varices by presenting a list of 52 pharmacological agents that reduce portal venous pressure and presented the advantages and disadvantages of each. He emphasized that recent randomized clinical trials (RCT) have demonstrated that propranolol delays and decreases the occurrence of haemorrhage from varices in patients who have not previously suffered such complications. He also reported that isosorbide-mononitrate is equally effective and further enhances the effect of propranolol. He also reported that the effects of propranolol plus endoscopic sclerotherapy (EST) were more effective than EST alone in preventing haemorrhage, but not in improving survival. Finally he noted that propranolol in high dosage did not prevent the development of large varices in cirrhotic patients with small or undetectable varices. Dr John Terblanche compared the efficacy of EST and endoscopic ligation of varices (ELV) and reported that all four RCTs found ELV to be superior. He discussed portacaval anastomosis (PCA) and concluded that only emergency PCA as reported by Orloff, is thought to be truly beneficial, and suggested that EST, plus ELV may be the treatment of choice. Dr Harold O. Conn, who served as the moderator of this session summarized the presentations and pointed out that liver transplantation is the most effective form of therapy of all, albeit extremely complex and expensive. He discussed transjugular intrahepatic portosystemic shunts (TIPS), the newest form of therapy, and emphasized its virtues (immediate reduction of portal venous pressure) and its limitations (frequent portosystemic encephalopathy and frequent spontaneous stenoses). He presented a brief discussion of the prevention of the development of the varices themselves, currently termed ‘pre-primary prophylaxis’, a hope for the future. He ended with ‘Predictions’ which if proven correct will give a preview of portal hypertension in the 21st century.