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2.  Lipooxygenase inhibition in osteoarthritis: a potential symptomatic and disease modifying effect? 
5-Loxin® is a compound extracted from an ancient herb that might be considered as a potent lipooxygenase inhibitor. The results observed in a preliminary trial suggest a highly intriguing clinically relevant symptomatic effect contrasting with a poor bioavailability of this compound. Moreover, in this trial, a statistically significant decrease in matrix metalloproteinase enzyme serum level suggests that, in addition to the observed symptomatic effect, such a compound might have a disease modifying effect in osteoarthritis. Further studies are required both to confirm the symptomatic efficacy and acceptable safety profile and to evaluate the potential chondromodulating effect of this compound.
doi:10.1186/ar2490
PMCID: PMC2592778  PMID: 18828886
4.  Interferon-induced versus chemokine transcripts as lupus biomarkers 
Compelling support for a central role for interferon-alpha in lupus pathogenesis has led to a new focus on the role of innate immune system activation in the generation of pathogenic mediators. These insights have been extended in translational studies of patients with well-characterized disease activity and clinical manifestations in order to identify informative molecular biomarkers. Chemokines are among the interferon-inducible genes, and new data support an association between the expression of chemokines and both lupus disease activity and organ damage. Longitudinal studies that relate molecular biomarkers to disease activity will be needed to validate these promising data and establish a sensitive measure of change for interventional studies and patient care.
doi:10.1186/ar2559
PMCID: PMC2656240  PMID: 19183425
5.  Plasma gelsolin as a biomarker of inflammation 
The prognostic implications of declining plasma gelsolin levels have been documented after a diverse variety of acute insults. Because gelsolin concentrations fall prior to the development of complications, a pathophysiological role for gelsolin depletion has been postulated in delayed multiorgan failure. The original hypothesis about the function of circulating gelsolin was that it scavenged actin released from cells at the site of injury. Although extracellular actin may be the primary cause of gelsolin depletion, the biologic imperative for gelsolin could entail the modulation of several inflammatory mediators as much as the disposal of actin. Translational research is actively addressing whether replenishment of plasma gelsolin could provide an efficacious and well tolerated therapeutic intervention in selected seriously ill patients.
doi:10.1186/ar2547
PMCID: PMC2656232  PMID: 19105851
6.  Vitamin D or hormone D deficiency in autoimmune rheumatic diseases, including undifferentiated connective tissue disease 
Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The presence of vitamin D receptors in the cells of the immune system and the fact that several of these cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties, and now potent immuno-mudulatory activities on dendritic cells, Th1 and Th17 cells, as well as B cells have been confirmed. Patients with undifferentiated connective tissue disease also show vitamin D deficiency and, interestingly, patients who progress into connective tissue diseases have lower vitamin D levels than those who remain in the undifferentiated connective tissue disease stage.
doi:10.1186/ar2552
PMCID: PMC2656237  PMID: 19090978
7.  Epitope spreading in animal models: array of hope in rheumatoid arthritis and multiple sclerosis 
The paradigm for pathogenic autoimmunity is the generation of high-titre, affinity-matured autoantibodies to a restricted family of autoantigens, in the appropriate genetic context. Genetic determinants of autoimmunity are largely found within the major histocompatibility complex (MHC) and the 'genotype to serotype to phenotype' concept is supported in a number of autoimmune diseases, where both genotype and serotype are well established. The serotype is autoantigen-driven, with evidence of epitope spreading as the disease evolves from asymptomatic to pathogenic autoimmunity. In rheumatoid arthritis and multiple sclerosis, where the autoantigens are poorly characterised, the use of an array in animal models may produce a hint of what happens in human disease. A more complete picture will be obtained from animals transgenic for human MHC, immunised with known human autoantigens.
doi:10.1186/ar2544
PMCID: PMC2656229  PMID: 19090965
10.  High-density lipoprotein: does it have a dark side? 
There are proven pleiotropic anti-atherogenic actions of high-density lipoprotein (HDL). However, in systemic inflammation, HDL can have pro-inflammatory properties that may contribute to accelerated atherosclerosis, likely mediated by a change in the structure of HDL to pro-inflammatory HDL (PiHDL). Validation of the technically challenging assay for PiHDL, and confirmation of an association of PiHDL in multiple populations with known risk for atherosclerosis will eventually provide a useful biomarker. Identification of PiHDL in patients with rheumatic disease may help identify patients at risk of accelerated atherosclerosis, and focus our therapeutic interventions.
doi:10.1186/ar2527
PMCID: PMC2592810  PMID: 19014411
12.  An important step towards completing the rheumatoid arthritis cycle 
In the previous issue of Arthritis Research & Therapy data are presented showing that circulating immune complexes containing citrullinated fibrin(ogen) are present in anti-citrullinated protein antibody-positive rheumatoid arthritis patients, and that such immune complexes co-localize with complement factor C3 in the rheumatoid synovium. These results corroborate the idea that citrullination is intimately involved in the pathophysiology of rheumatoid arthritis and complete our model (the rheumatoid arthritis cycle) for the development and chronic nature of this disease.
doi:10.1186/ar2504
PMCID: PMC2592789  PMID: 18828887
13.  Suppression of bone morphogenetic protein inhibitors promotes osteogenic differentiation: therapeutic implications 
Bone morphogenetic proteins (BMPs) are expressed during osteogenesis and their action is regulated by corresponding BMP inhibitors. Chordin (a well recognized BMP inhibitor) and BMP-2 are expressed during osteogenic differentiation of human mesenchymal stem cells. Chordin inhibition induces human mesenchymal stem cell differentiation and reduces their proliferation by increasing BMP-2 bioavailability. The potential of suppressing BMP inhibitors is emerging as a biological therapeutic target in bone tissue engineering, because it results in an unopposed synergy between the various growth factors that are involved in osteogenesis, within their physiological milieu.
doi:10.1186/ar2467
PMCID: PMC2575635  PMID: 18710600
14.  Altered fractalkine cleavage results in an organ-specific 17 kDa fractalkine fragment in salivary glands of NOD mice 
Sjögren's syndrome is a rheumatic disease in which the salivary and lacrimal glands are the principal targets of a pathological autoimmune reaction. Previous studies in mice indicated that delayed organogenesis and aberrant cell physiology followed by an increase in acinar cell apoptosis precede chronic focal inflammation in the salivary glands and the manifestation of impaired exocrine gland secretion. In a recent study by Wildenberg and colleagues, the authors report aberrant proteolytic activity in the salivary glands of non-obese diabetic mice and the generation of a unique organ-specific 17 kDa fragment of the chemokine and adhesion molecule fractalkine.
doi:10.1186/ar2458
PMCID: PMC2575630  PMID: 18710591
15.  Paradoxical effects of tumour necrosis factor-α in adjuvant-induced arthritis 
Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses.
doi:10.1186/ar2430
PMCID: PMC2483450  PMID: 18564403
16.  Gout in the spotlight 
Understanding how uric acid crystals provoke inflammation is crucial to improving our management of acute gout. It is well known that urate crystals stimulate monocytes and macrophages to elaborate inflammatory cytokines, but the tissue response of the synovium is less well understood. Microarray analysis of mRNA expression by these lining cells may help to delineate the genes that are modulated. Employing a murine air-pouch model, a number of genes expressed by innate immune cells were found to be rapidly upregulated by monosodium urate crystals. These findings provide new research avenues to investigate the physiopathology of gouty inflammation, and may eventually lead to new therapeutic targets in acute gout.
doi:10.1186/ar2396
PMCID: PMC2483432  PMID: 18564404
17.  High mobility group box-1 protein as a tumor necrosis factor-independent therapeutic target in rheumatoid arthritis 
Rheumatoid arthritis (RA) remains a prevalent disease worldwide that causes significant morbidity and mortality despite recent therapeutics. High mobility group box-1 (HMGB1) protein, originally appreciated as an intranuclear DNA binding protein, has been implicated as an integral mediator in the pathogenesis of animal arthritides and RA disease in humans. Our current understanding of HMGB1 has promoted the development of targeting therapies that have improved outcomes in animal models of inflammation. In the previous issue of Arthritis Research & Therapy, Sundberg and colleagues address, for the first time in a prospective cohort study, whether HMGB1 expression is dependent upon tumor necrosis factor activity in patients with RA.
doi:10.1186/ar2427
PMCID: PMC2483447  PMID: 18557992
19.  The relationship between cancer and rheumatoid arthritis: still a large research agenda 
The association between rheumatoid arthritis (RA) and malignancies has received increased attention in recent years. Reports suggesting that tumor necrosis factor blockers might elevate the risk of malignancy in RA patients have prompted researchers to look at the incidence of malignancies in all RA patients. In a recent issue of Arthritis Research & Therapy, Smitten and colleagues suggest that previous reports of a standardized incidence ratio close to one for malignancies in RA may reflect an increased risk for some site-specific malignancies and a reduced risk for others. Here we discuss these findings and suggest what issues could be addressed in future studies.
doi:10.1186/ar2417
PMCID: PMC2483437  PMID: 18495048
20.  Mechanisms of oral tolerance revisited 
Oral tolerance induction is thought to depend on special antigen presenting cells in the gut. A new report in the previous issue of Arthritis Research & Therapy supports this idea by demonstrating that indoleamine 2,3-dioxygenase-expressing dendritic cells in Peyer's patches from orally tolerized mice suppress T-cell responses via the generation of CD4+CD25+ regulatory T cells. This finding provides novel input into the mechanisms of oral tolerance that could further facilitate its use for the treatment of autoimmunity and chronic inflammatory reactions.
doi:10.1186/ar2402
PMCID: PMC2453763  PMID: 18466643
21.  Role of interleukin-7 in degenerative and inflammatory joint diseases 
IL-7 is known foremost for its immunostimulatory capacities, including potent T cell-dependent catabolic effects on bone. In joint diseases like rheumatoid arthritis and osteoarthritis, IL-7, via immune activation, can induce joint destruction. Now it has been demonstrated that increased IL-7 levels are produced by human articular chondrocytes of older individuals and osteoarthritis patients. IL-7 stimulates production of proteases by IL-7 receptor-expressing chondrocytes and enhances cartilage matrix degradation. This indicates that IL-7, indirectly via immune activation, but also by a direct action on cartilage, contributes to joint destruction in rheumatic diseases.
doi:10.1186/ar2395
PMCID: PMC2453758  PMID: 18466642
22.  Exogenous tumour necrosis factor α induces suppression of autoimmune arthritis 
Introduction
Our previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)α in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high TNFα levels and reduced severity of arthritis. To further explore this correlation, we compared the TNFα secretion profile of the AA-resistant Wistar Kyoto (WKY) rats with that of LEW rats, determined the effect of exogenous TNFα on the course of AA in LEW rats, and examined various mechanisms involved in TNFα-induced disease modulation.
Methods
A cohort each of LEW and WKY rats was immunised subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra (Mtb). At different time points thereafter, subgroups of rats were killed and their draining lymph node cells were tested for cytokine production. Another group of LEW rats was injected with TNFα intraperitoneally daily for a total of 10 injections, 3 before and 6 after Mtb challenge, and then observed for signs of AA. In parallel, TNFα-treated rats were examined for changes in other cytokines, in CD4+CD25+ T cell frequency, and in indoleamine 2,3-dioxygenase (IDO) mRNA expression levels.
Results
LEW rats displayed a TNFα secretion profile that was opposite to that of the WKY rats. Furthermore, TNFα treatment significantly downmodulated the severity of AA in LEW rats, and decreased the interferon (IFN)-γ secretion in response to the pathogenic determinant of the disease-related antigen. No significant alterations were observed in other parameters tested.
Conclusion
The role of endogenous TNFα in the induction and propagation of arthritis is well established. However, exogenous TNFα can downmodulate the course of AA, displaying an immunoregulatory functional attribute of this cytokine.
doi:10.1186/ar2393
PMCID: PMC3386491  PMID: 18380898
23.  Rheumatologists, take heart! We may be doing something right 
In the present issue of Arthritis Research & Therapy data are presented suggesting that antirheumatic therapies decrease the risk of cardiovascular disease in patients with rheumatoid arthritis. The QUEST-RA group, a large international collaboration, analyzed data on 4,363 patients in a cross-sectional manner. Traditional risk factors were all significantly associated with cardiovascular events, and the presence of extraarticular disease significantly increased the risk, confirming a previous publication. The most interesting analysis in this study suggests that effective antirheumatic treatment, with traditional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, or anti-TNF biologics, reduces the risk of cardiovascular disease in rheumatoid arthritis. Some methodological issues are discussed, however, and confirmatory studies are suggested.
doi:10.1186/ar2364
PMCID: PMC2453770  PMID: 18341711
24.  Comparing the prevalence of rheumatic diseases in China with the rest of the world 
Geographic or ethnic differences in the occurrence of disease often provide insights into causes of disease and possible opportunities for disease prevention. Persons in China appear to have a consistently lower prevalence of rheumatoid arthritis and fibromyalgia than persons in the United States and Europe; reasons for these prevalence differences might include genetic differences, differences in environmental exposures or a combination of both. With increasing obesity, gout is becoming endemic in China. Finally, symptomatic knee osteoarthritis is extremely common in China and constitutes a major public health problem there.
doi:10.1186/ar2369
PMCID: PMC2374465  PMID: 18341701
25.  Complement and arthritis: another step in understanding 
In a recent research article in Arthritis Research and Therapy ('Analysis of C204 and the C4 binding protein in the MRL/lpr mouse'), Wenderfer and colleagues report that deficiency in C4 binding protein, a down-regulator of the classic pathway of complement, does not affect the development of autoimmune disease. These data support the earlier finding that the alternative pathway, and not the classic pathway, drives disease progression. However, in a milder variant of the MRL/lpr model, the lpr/lpr mouse, classic pathway deficiency does contribute toward renal pathology and more severe disease. In this editorial we discuss the factors that may cause such a discrepancy.
doi:10.1186/ar2359
PMCID: PMC2374468  PMID: 18304382

Results 1-25 (222)