Different Stages Of Arthritis Research Articles

Effects of triterpenoid and iridoid of Eucommiae Cortex on collagen-induced arthritis in rats

The ethyl acetate fraction of ethanol extract of Eucommiae Cortex can effectively inhibit joint inflammation and bone destruction in rats with collagen-induced arthritis(CIA) and has a potential therapeutic effect on rheumatoid arthritis. The triterpenoid(EU-Tid) and iridoid(EU-Idd) of Eucommiae Cortex are derivatives isolated from the ethyl acetate fraction of the ethanol extract of Eucommiae Cortex, and it is not clear whether they have inhibitory effects on joint inflammation and bone erosion in CIA rats. Therefore, based on the CIA model, the effects of EU-Tid, EU-Idd, and their combination(EU-TP) on arthritis in rats were observed, and the material basis of Eucommiae Cortex against arthritis was further clarified. The samples were collected two and four weeks after administration to observe the pathological changes in different stages of arthritis in CIA rats. For the rats in the model control group, with the prolongation of the disease course, the paw volume and arthritis score increased and histopathological lesions aggravated. Compared with the model control group, the drug administration groups showed reduced paw volumes and arthritis scores, and improved joint lesions and cartilage destruction. Additionally, the mRNA expression levels of tumor necrosis factor-α(TNF-α), interleukin-17(IL-17), and interleukin-23(IL-23) in the spleen were down-regulated in the drug administration groups. EU-TP and EU-Tid at concentrations of 160 and 320 μg·mL~(-1) could significantly inhibit the proliferation of human fibroblast-like synoviocytes-RA(HFLS-RA) and nitric oxide(NO) release in the supernatant of RAW264.7 cells induced by lipopolysaccharide(LPS) at the concentration range of 10-80 μg·mL~(-1) in vitro. EU-Idd had no effect on the proliferation of HFLS-RA but could reduce the NO release at concentrations of 40 and 80 μg·mL~(-1). The results indicated that the terpenoids of Eucommiae Cortex had great potential in the treatment of rheumatoid arthritis.

Implication of herbal medicines for curing arthritis in Central Western Ghats of Karnataka

Background: The study area lies in the Central Western Ghats which is one of the 36 biodiversity hotspots of the world. Over 4.5 billion people in developing countries and overall 60% of the world population rely on traditional medicine as components of their healthcare. Documentation of such traditional medicinal knowledge is important for conservation of medicinal plants and as well as future beneficiaries. Methods: A purposive sampling method was adapted. A self-structured questionnaire was used to collect the feedbacks of patients. The information (plant parts, mode of usage, dosage) were collected through face to face interviews and discussions with the traditional practitioners. The medicinal plants used were collected for herbarium preparation and identified using standard regional and district floras. Results: A total of 15 medicinal plant species belonging to 11 families for treating arthritis were found in this study. The dominant habit was climbing shrub. Leaves were used in higher proportion (63%). The members of Lamiaceae family were dominant. Three important formulations (pellet, decoction, oil) were used to treat different stages of Arthritis. The statistical outcome from the patients’ feedback questionnaire is also mentioned in the paper. Conclusions: Herbal preparations should only be prepared as remedy by a practitioner. The people in and around the study area depend on traditional medicine given by practitioner for arthritis. The conservation of such traditional knowledge for treatment can only be accomplished through systematic documentation and scientific research. Keywords: Diversity , Ethnobotany, Herbal medicine, Joint pain, Medicinal plants, Sharavathi valley, Traditional medicine.

AB0111 Role of Toll-Like Receptor 9 in the Pathogenesis of Inflammatory Autoimmune Arthritis and Osteoclast Activation

BackgroundThere is some evidence that release and insufficient removal of endogenous nucleic acids may be involved in triggering harmful autoimmune reactions that might be important in the initiation of RA....

4.8 Role of Toll-like receptor 9 in the pathogenesis of inflammatory autoimmune arthritis and osteoclast activation

Background and ObjectivesThere is some evidence that release and insufficient removal of endogenous nucleic acids may be involved in triggering harmful autoimmune reactions that might be important in the initiation...

A1.44 Fibroblasts lose their immunosuppressive ability early in the development of rheumatoid arthritis: effects on lymphocyte recruitment

ObjectivesFibroblasts actively regulate the recruitment of leukocytes by endothelial cells (EC), acting in a pro- or anti-inflammatory manner depending on their site of origin. The phenotype of the fibroblast may...

Relationship between serum IL10 level and p38MAPK enzyme activity on behavioral and cellular aspects of variation of hyperalgesia during different stages of arthritis in rats

Regarding to anti-inflammatory role of interleukin (IL) 10, its inhibitory effects on p38MAPK activity and, different pro and anti-inflammatory roles of activated p38MAPK in cells, this study was aimed to investigate relationship between serum IL10 level and p38MAPK enzyme activity on behavioral and cellular aspects variation of hyperalgesia during different stages of arthritis in rats. Adjuvant arthritis (AA) was induced by a single subcutaneous injection of complete Freund's adjuvant into the rats' hind paw. Behavioral and inflammatory responses were assessed at 0, 3, 7, 14, and 21days of study. Receptor and other protein enzyme expression variations were detected by western blotting. Anti-IL10 and p38MAPK inhibitor were administered daily during the 21days of study. Daily treatment with anti-IL10 antibody significantly increased paw edema and hyperalgesia in the AA group compared with the AA control group. Administration of anti-IL10 antibody caused significant increase in the ratio of phosphorylated p38 to p38MAPK enzyme level expression on 14th and 21st days of study compared with the AA control group. Our study confirmed that a part of anti- inflammatory effects of serum IL10 during AA inflammation was mediated via inhibition of p38MAPK enzyme phosphorylation. Moreover, these findings suggest that increase in the level of spinal mu opioid receptor expression during AA inflammation is not mediated via the direct effect of serum IL10 on spinal p38MAPK.

Cellular events during arthritis-induced hyperalgesia are mediated by Interleukin-6 and p38 MAPK and their effects on the expression of spinal mu-opioid receptors

Activation of mitogen-activated protein kinase (MAPK) enzymes in nociceptive plasticity has been extensively studied. P38 MAPK enzyme, which can be activated by cytokines, acts as a crucial intracellular regulator of environmental changes. The aim of this study was to elucidate the cellular events during arthritis-induced hyperalgesia that are mediated by interleukin-6 and p38 MAPK, and their effects on the expression of spinal mu-opioid receptors (MORs), in different stages of arthritis in male Wistar rats. Complete Freund's adjuvant (CFA)-induced arthritis (AA) was caused by subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 antibody and p38 MAPK phosphorylation inhibitor were administered during 21 days of study. Spinal MOR, p38, and phosphorylated-p38 (pp38) proteins expressions were detected by Western blotting. Daily treatment with anti-IL-6 antibody and p38 MAPK phosphorylation inhibitor, SB203580, significantly decreased paw edema in AA group. Daily anti-IL-6 and SB203580 administration caused a significant reduction in hyperalgesia in the first week of the study, but increased hyperalgesia in the next 2 weeks in experimental groups compared to the AA control group. Expression of pp38 MAPK protein significantly decreased on the 3, 7, 14, and 21 days in AA+SB203580 and AA+anti-IL6 groups compared to AA group. Additionally, daily treatment with anti-IL6 antibody and SB203580 in AA group caused significantly decrease in spinal MOR expression compared to AA control group. The results of our study can confirm that activated spinal p38 MAPK enzyme may play an important role in cellular IL-6 signaling pathways in hyperalgesia variation during different stages of AA inflammation. Also, it can be suggested that at least a part of p38 MAPK effects on hyperalgesia is mediated by spinal MOR expression variation.

A1.2 Fibroblasts Influence Lymphocyte Recruitment and Migration During Resolving and Persistent Arthritis

Background and ObjectivesFibroblasts actively regulate the recruitment of leukocytes by endothelial cells (EC), acting in a pro- or anti-inflammatory manner depending on their site of origin. The phenotype of the...

In Vivo Imaging of Cell Proliferation Enables the Detection of the Extent of Experimental Rheumatoid Arthritis by 3′-Deoxy-3′-18F-Fluorothymidine and Small-Animal PET

The aim of this work was to study the feasibility of measuring cell proliferation noninvasively in vivo during different stages of experimental arthritis using the PET proliferation tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT). We injected mice with serum containing glucose-6-phosphate-isomerase-specific antibodies to induce experimental arthritis, and we injected control mice with control serum. Animals injected with (18)F-FLT 1, 3, 6, and 8 d after the onset of disease were analyzed in vivo by PET, PET/CT, or PET/MR imaging followed by autoradiography analysis. The (18)F-FLT uptake in the ankles and forepaws was quantified on the basis of the PET images by drawing standardized regions of interest. To correlate the in vivo PET data with cell proliferation, we performed Ki-67 immunohistochemistry of diseased and healthy joints at the corresponding time points. Analysis of the different stages of arthritic joint disease revealed enhanced (18)F-FLT uptake in arthritic ankles (2.2 ± 0.2 percentage injected dose per gram [%ID/g]) and forepaws (2.1 ± 0.3 %ID/g), compared with healthy ankles (1.4 ± 0.3 %ID/g) and forepaws (1.5 ± 0.5 %ID/g), as early as 1 d after the glucose-6-phosphate-isomerase serum injection, a time point characterized by clear histologic signs of arthritis but only slight ankle swelling. The (18)F-FLT uptake in the ankles (3.5 ± 0.3 %ID/g) reached the maximum observed level at day 8. Ki-67 immunohistochemical staining of the arthritic ankles and forepaws revealed a strong correlation with the in vivo (18)F-FLT PET data. PET/CT and PET/MR imaging measurements enabled us to identify whether the (18)F-FLT uptake was located in the bone or the soft tissue. Noninvasive in vivo measurement of cell proliferation in experimental arthritis using (18)F-FLT PET is a promising tool to investigate the extent of arthritic joint inflammation.

Tumor necrosis factor–interleukin‐17 interplay induces S100A8, interleukin‐1β, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: Rationale for combination treatment during arthritis

To examine whether synovial interleukin-17 (IL-17) expression promotes tumor necrosis factor (TNF)-induced joint pathologic processes in vivo, and to analyze the surplus ameliorative value of neutralizing IL-17 in addition to TNF during collagen-induced arthritis (CIA). Adenoviral vectors were used to induce overexpression of IL-17 and/or TNF in murine knee joints. In addition, mice with CIA were treated, at different stages of arthritis, with soluble IL-17 receptor (sIL-17R), TNF binding protein (TNFBP), or the combination. Overexpression of IL-17 and TNF resulted in joint inflammation and bone erosion in murine knees. Interestingly, IL-17 strikingly enhanced both the joint-inflammatory and joint-destructive capacity of TNF. Further analysis revealed a strongly enhanced up-regulation of S100A8, IL-1β, and matrix metalloproteinase (MMP) messenger RNA, only when both TNF and IL-17 were present. Moreover, the increase in irreversible cartilage destruction was not merely the result of enhanced inflammation, but also was associated with a direct synergistic effect of these cytokines in the joint. S100A9 deficiency in mice protected against IL-17/TNF-induced expression of cartilage NITEGE neoepitopes. During established arthritis, the combination of sIL-17R and TNFBP was more effective than the anticytokine treatments alone, and significantly inhibited further joint inflammation and cartilage destruction. Local synovial IL-17 expression enhances the role of TNF in joint destruction. Synergy between TNF and IL-17 in vivo results in striking exaggeration of cartilage erosion, in parallel with a synergistic up-regulation of S100A8, IL-1β, and erosive MMPs. Moreover, neutralizing IL-17 in addition to TNF further improves protection against joint damage and is still effective during late-stage CIA. Therefore, compared with anti-TNF alone, combination blocking of TNF and IL-17 may have additional therapeutic value for the treatment of destructive arthritis.

Education for arthritis patients: a community pharmacy based pilot project.

There are different kinds of arthritis, widely spread among the population, that make them a clinical problem with social, psychological and economic burden. Different education programs have been developed in order to improve patients' disease management, medication compliance and from there patients' quality of life. To develop and implement a community pharmacy-based educational program for patients with arthritis. Improvements in pain, medication compliance, decrease in general practitioner's visits and hospitalizations are expected. Prospective, randomized, controlled trial. The sample consisted of 43 individuals, with different stages of arthritis (aged 15 - 71), attending pharmacies - intervention group; and 43 individuals - control group. A 4-month education was conducted on the following topics: what causes arthritis and what are the factors that can intensify it; pain management and physical activities; self-management and prevention; pharmacotherapy and possible adverse drug reactions. Patient's health-related quality of life was assessed in the beginning and at the end of the survey. PARAMETERS ASSESSED DURING THE FOUR STAGES OF THE PROGRAM WERE: frequency of severe pain, frequency of general practitioner's visits, frequency of urgent medical aid calls, compliance with therapy, satisfaction with pharmacy services. Improvement in patients' health-related quality of life was observed and also: decrease in the severity of patients' pain, decrease in the physician's visits, and increase in satisfaction overall care. Positive results from the educational approach in pharmacy conditions were demonstrated. These consequences have a potential to increase arthritis patient's quality of life.

Increased number and function of FoxP3 regulatory T cells during experimental arthritis

CD4+CD25+FoxP3+ regulatory T (Treg) cells are critical regulators of autoimmunity. Yet the number of Treg cells is paradoxically increased in rheumatoid arthritis (RA) patients, and Treg cells show variable activity in human studies. The objective of this study was to characterize the expansion and function of Treg cells during the initiation and progression of experimental arthritis. To unequivocally identify Treg cells, we crossed FoxP3gfp mice with K/BxN mice to generate arthritic mice in which Treg cells express green fluorescence protein. We examined the expansion and function of Treg cells and effector T (Teff) cells during different stages of arthritis, using flow cytometry and cell proliferation analyses. In K/BxN mice, thymic selection of KRN T cells resulted in an enrichment of forkhead box P3 (FoxP3)-positive Treg cells. Treg cell numbers increased during arthritis, with significant increases in spleens and draining lymph nodes, indicating selective tropism to sites of disease. In contrast to the in vitro unresponsiveness of Treg cells when cultured alone, substantial proportions of Treg cells proliferated in both nonarthritic and arthritic mice. However, they also underwent greater apoptosis, thereby maintaining equilibrium with Teff cells. Similarly, enhanced Treg cell-suppressive activity during arthritis was offset by greater resistance by their Teff cell counterparts and antigen-presenting cells. In this well-established model of RA, the interplay of Teff cells and Treg cells in K/BxN mice recapitulated many features of the human disease. We demonstrated an ordered expansion of Treg cells during arthritis and dynamic changes in Treg cell and Teff cell functions. By elucidating factors that govern Treg cell and Teff cell development in K/BxN(gfp) mice, we will gain insight into the pathophysiology of and develop novel therapeutics for human RA.

Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity

Autoantibodies directed against citrulline-containing proteins have an impressive specificity of nearly 100% in patients with rheumatoid arthritis and have been suggested to be involved in the disease pathogenesis. The targeted epitopes are generated by a post-translational modification catalysed by the calcium-dependent enzyme peptidyl arginine deiminase (PAD), which converts positively charged arginine to polar but uncharged citrulline. The aim of this study was to explore the effects of citrullination on the immunogenicity of autoantigens as well as on potential arthritogenicity. Thus, immune responses to citrullinated rat serum albumin (Cit-RSA) and to unmodified rat serum albumin (RSA) were examined as well as arthritis development induced by immunisation with citrullinated rat collagen type II (Cit-CII) or unmodified CII. In addition, to correlate the presence of citrullinated proteins and the enzyme PAD4 with different stages of arthritis, synovial tissues obtained at different time points from rats with collagen-induced arthritis were examined immunohistochemically. Our results demonstrate that citrullination of the endogenous antigen RSA broke immunological tolerance, as was evident by the generation of antibodies directed against the modified protein and cross-reacting with the native protein. Furthermore we could demonstrate that Cit-CII induced arthritis with higher incidence and earlier onset than did the native counterpart. Finally, this study reveals that clinical signs of arthritis precede the presence of citrullinated proteins and the enzyme PAD4. As disease progressed into a more severe and chronic state, products of citrullination appeared specifically in the joints. Citrullinated proteins were detected mainly in extracellular deposits but could also be found in infiltrating cells and on the cartilage surface. PAD4 was detected in the cytoplasm of infiltrating mononuclear cells, from day 21 after immunisation and onwards. In conclusion, our data reveal the potency of citrullination to break tolerance against the self antigen RSA and to increase the arthritogenic properties of the cartilage antigen CII. We also show that citrullinated proteins and the enzyme PAD4 are not detectable in healthy joints, and that the appearance and amounts in arthritic joints of experimental animals are correlated with the severity of inflammation.

Appearance of calpain correlates with arthritis and cartilage destruction in collagen induced arthritic knee joints of mice.

To determine the relevance of calpain in murine collagen induced arthritis (CIA) and to correlate the presence of m-calpain with the appearance of arthritis and cartilage destruction. The immunohistochemical appearance and localisation of m-calpain at different stages of arthritis were analysed and compared with the histological changes occurring during type II CIA. The arthritic knee joint lavage was also examined for m-calpain by immunoelectrophoretic blotting. Immunohistochemical staining demonstrated a clear positive correlation between the appearance of m-calpain and both a histological grade of arthritis and an acute phase of cartilage destruction. Further development of the disease showed continual presence of m-calpain but with reduced intensity. Intra-articular inflammatory cells (mainly polymorphonuclear leucocytes, synovial lining cells, and sublining fibroblasts) were found to be the most positively stained, but extracellular localisation of m-calpain on the surface of cartilage and synovium, and in the articular cartilage matrix and chondrocyte lacunae, was also observed. In the knee joint lavage obtained at the most intensive stage of acute arthritis, m-calpain was detectable by immunoelectrophoretic blotting. The findings suggest that m-calpain may act at an early phase of CIA as a matrix proteinase and take part in the destruction of articular cartilage or activate other destructive enzymes.