Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis.

OBJECTIVES: Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Hexokinases (HKs) catalyse the first step in glucose metabolism, and HK2 constitutes the principal HK inducible isoform. We hypothesise that HK2 contributes to the synovial lining hypertrophy and plays a critical role in bone and cartilage damage. METHODS: HK1 and HK2 expression were determined in RA and osteoarthritis (OA) synovial tissue by immunohistochemistry. RA FLS were transfected with either HK1 or HK2 siRNA, or infected with either adenovirus (ad)-GFP, ad-HK1 or ad-HK2. FLS migration and invasion were assessed. To study the role of HK2 in vivo, 108 particles of ad-HK2 or ad-GFP were injected into the knee of wild-type mice. K/BxN serum transfer arthritis was induced in HK2F/F mice harbouring Col1a1-Cre (HK2Col1), to delete HK2 in non-haematopoietic cells. RESULTS: HK2 is particular of RA histopathology (9/9 RA; 1/8 OA) and colocalises with FLS markers. Silencing HK2 in RA FLS resulted in a less invasive and migratory phenotype. Consistently, overexpression of HK2 resulted in an increased ability to migrate and invade. It also increased extracellular lactate production. Intra-articular injection of ad-HK2 in normal knees dramatically increased synovial lining thickness, FLS activation and proliferation. HK2 was highly expressed in the synovial lining after K/BxN serum transfer arthritis. HK2Col1 mice significantly showed decreased arthritis severity, bone and cartilage damage. CONCLUSION: HK2 is specifically expressed in RA synovial lining and regulates FLS aggressive functions. HK2 might be an attractive selective metabolic target safer than global glycolysis for RA treatment.

The role of molecular pain biomarkers in temporomandibular joint internal derangement.

There is evidence that low-grade inflammation may be responsible for pain and development of degenerative changes in temporomandibular joint internal derangement. This article reviews the current knowledge of the molecular mechanisms behind TMJ internal derangements. A non-systematic search was carried out in PubMed, Embase and the Cochrane library for studies regarding pathophysiological mechanisms behind internal derangements focusing on pain-mediating inflammatory and cartilage-degrading molecules. Recent data suggest that release of cytokines may be the key event for pain and cartilage destruction in TMJ internal derangements. Cytokines promote the release of matrix metalloproteinases (MMPs), and due to hypoxia, vascular endothelial growth factor (VEGF) is released. This activates chondrocytes to produce MMPs and reduce their tissue inhibitors (TIMPs) as well as the recruitment of osteoclasts, ultimately leading to cartilage and bone resorption. Also, proteoglycans have an important role in this process. Several cytokines, MMPs, TIMPs and VEGF have been identified in higher concentrations in the TMJ synovial fluid of patients with painful internal derangements and shown to be associated with the degree of degeneration. Other molecules that show elevated levels include hyaluronic acid synthase, disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), aggrecan, fibromodulin, biglycan and lumican. Taken together, more or less pronounced inflammation of TMJ structures with release of cytokines, MMPs and other molecular markers that interact in a complex manner may be responsible for tissue degeneration in internal derangements. As internal derangements may be symptom-free, the degree of inflammation, but also other mechanisms, may be important for pain development.

Synovitis biomarkers: ex vivo characterization of three biomarkers for identification of inflammatory osteoarthritis.

OBJECTIVE: Characterize biomarkers measuring extracellular matrix turnover of inflamed osteoarthritis synovium. METHODS: Human primary fibroblast-like synoviocytes and synovial membrane explants (SMEs) treated with various cytokines and growth factors were assessed by C1M, C3M, and acMMP3 in the conditioned medium. RESULTS: TNFα significantly increased C1M up to seven-fold (p = 0.0002), C3M up to 24-fold (p = 0.0011), and acMMP3 up to 14-fold (p < 0.0001) in SMEs. IL-1ß also significantly increased C1M up to five-fold (p = 0.00094), C3M four-fold (p = 0.007), and acMMP3 18-fold (p < 0.0001) in SMEs. CONCLUSION: The biomarkers C1M, C3M, and acMMP-3 were synovitis biomarkers ex vivo and provide a translational tool together with the SME model.

Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis.

OBJECTIVE: To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA). METHODS: Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15. RESULTS: The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn's synovitis score (r = 0.574, P < 0.001) and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RA (r = 0.656, P < 0.001). Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (all P < 0.05). CONCLUSION: Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis.

T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice.

OBJECTIVE: T cell protein tyrosine phosphatase (TC-PTP) is an important regulator of hematopoiesis and cytokine signaling. Recently, several genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) in the locus of TC-PTP that are associated with rheumatoid arthritis and juvenile idiopathic arthritis, among other autoimmune diseases. The aim of this study was to evaluate the effect of TC-PTP deficiency on the bone and joint environment using a knockout mouse model. METHODS: Radiographic and micro-computed tomography analyses were performed on femurs of 3-week-old mice. In addition, the femorotibial joints were assessed by histology, flow cytometry, and cytokine detection. RESULTS: Deficiency of TC-PTP resulted in decreased bone volume as well as an increase in osteoclast density within the mouse femurs. In addition, synovitis, characterized by infiltration of mixed inflammatory cell types and proinflammatory cytokines, developed in the knee joints of TC-PTP(-/-) mice. CONCLUSION: These findings demonstrate that loss of TC-PTP expression results in synovitis with several hallmarks of inflammatory arthritis. The inflammatory environment observed in the knee joints of TC-PTP(-/-) mice differs from the systemic inflammation previously described in these mice and merits further research into the role of TC-PTP in the synovium. Furthermore, the results support recently described associations between SNPs in the TC-PTP locus and arthritis incidence.

Platelets participate in synovitis via Cox-1-dependent synthesis of prostacyclin independently of microparticle generation.

In addition to the well-described role of platelets in thrombosis, a growing body of evidence implicates platelets in diverse inflammatory responses. We recently showed platelets can contribute to the pathophysiology of inflammatory arthritis via IL-1- containing microparticles. In this study, we demonstrate that platelets, and not platelet microparticles, actively contribute to synovitis via production of proinflammatory prostacyclin in an autoimmune arthritis model. Using both genetic and pharmacologic approaches, we establish that paracrine production of prostacyclin proceeds in the absence of cyclooxygenase-2. Furthermore, we also demonstrate that prostacyclin generation can arise via transcellular collaboration between platelets and fibroblast-like synoviocytes. In addition to shedding light on an unappreciated pathway of lipid synthesis in arthritis, we further delineate a novel effector activity by which platelets can contribute to inflammatory disease.

Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.

Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-alpha-induced arthritis.

Sphingosine kinase 1 (SphK1) is an enzyme that converts sphingosine to bioactive sphingosine-1-phosphate. Recent in vitro data suggest a potential role of SphK1 in TNF-alpha-mediated inflammation. Our aims in this study were to determine the in vivo significance of SphK1 in TNF-alpha-mediated chronic inflammation and to define which pathogenic mechanisms induced by TNF-alpha are SphK1 dependent. To pursue these aims, we studied the effect of SphK1 deficiency in an in vivo model of TNF-alpha-induced chronic inflammatory arthritis. Transgenic hTNF-alpha mice, which develop spontaneous inflammatory erosive arthritis beginning at 14-16 wk, were crossed with SphK1 null mice (SphK1(-/-)), on the C57BL6 genetic background. Beginning at 4 mo of age, hTNF/SphK1(-/-) mice had significantly less severe clinically evident paw swelling and deformity, less synovial and periarticular inflammation, and markedly decreased bone erosions as measured quantitatively through micro-CT images. Mechanistically, the mice lacking SphK1 had less articular cyclooxygenase 2 protein and fewer synovial Th17 cells than did hTNF/SphK1(+/+) littermates. Microarray analysis and real-time RT-PCR of the ankle synovial tissue demonstrated that hTNF/SphK1(-/-) mice had increased transcript levels of suppressor of cytokine signaling 3 compared with hTNF/SphK1(+/+) mice, likely also contributing to the decreased inflammation in the SphK1-deficient mice. Finally, significantly fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1(-/-) mice compared with hTNF/SphK1(+/+) mice. These data indicate that SphK1 plays a key role in hTNF-alpha-induced inflammatory arthritis via impacting synovial inflammation and osteoclast number.

Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane.

BACKGROUND: The cAMP-metabolising enzyme, phosphodiesterase 4 (PDE4), has been implicated in a number of immune responses, including tumour necrosis factor α (TNFα) production. To date, few data have directly addressed whether synovial cytokine and chemokine production is modified by PDE4. OBJECTIVE: Using specific PDE4 inhibitors, roflumilast plus two novel inhibitors, INH 0061 and INH 0062, the authors studied the effect of PDE4 inhibition on proinflammatory cytokine and chemokine release from primary rheumatoid arthritis (RA) synovial digest suspensions and in a macrophage T cell co-culture assay system. RESULTS: All PDE4 inhibitors dose-dependently reduced the release of TNFα from primary synovial membrane cultures (n=5), half maximal inhibitory concentration (IC(50)) 300-30 nM, p<0.05. Similarly, a significant suppression in the release the proinflammatory chemokines, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß (IC(50) 300-30 nM) and regulated upon activation normal T-cell expressed and secreted (RANTES) (IC(50) 3 nM) was also observed, p<0.05. While interleukin 1ß was also reduced, it did not achieve an IC(50). These observations were further confirmed in a macrophage T cell co-culture system, demonstrating the importance of PDE4 pathways in regulating cytokine/chemokine release in a cellular interaction implicated in inflammatory synovitis. Subsequent studies using the human monocytic cell line U937 also demonstrated cytokine regulation with PDE4 knockdown utilising a small interfering RNA approach. CONCLUSION: These data provide direct evidence of PDE4-dependent pathways in human RA synovial inflammatory cytokine and chemokine release and may provide a novel approach in treating chronic autoimmune conditions such as RA.

Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis.

Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-alpha and LTbeta, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTalpha3 homotrimers are secreted, whereas LTalpha(1)beta(2) heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTalphabeta heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTalphabeta heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTalpha3 and TNFalpha. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor. Soluble LTalphabeta was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTalphabeta in RA patient synovial fluid correlated with increased TNFalpha, IL-8, IL-12, IL-1beta, IFN-gamma, and IL-6 cytokines. Moreover, recombinant LTalpha1beta2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTalphabeta in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.

Non-Transcriptional and Translational Function of Canonical NF-κB Signaling in Activating ERK1/2 in IL-1ß-Induced COX-2 Expression in Synovial Fibroblasts.

The pro-inflammatory cytokine interleukin 1ß (IL-1ß) induces the synthesis of prostaglandin E2 by upregulating cyclooxygenase-2 (COX-2) in the synovial tissue of individuals with autoimmune diseases, such as rheumatoid arthritis (RA). IL-1ß-mediated stimulation of NF-κB and MAPK signaling is important for the pathogenesis of RA; however, crosstalk(s) between NF-κB and MAPK signaling remains to be understood. In this study, we established a model for IL-1ß-induced synovitis and investigated the role of NF-κB and MAPK signaling in synovitis. We observed an increase in the mRNA and protein levels of COX-2 and prostaglandin E2 release in cells treated with IL-1ß. NF-κB and ERK1/2 inhibitors significantly reduced IL-1ß-induced COX-2 expression. IL-1ß induced the phosphorylation of canonical NF-κB complex (p65 and p105) and degradation of IκBα. IL-1ß also induced ERK1/2 phosphorylation but did not affect the phosphorylation levels of p38 MAPK and JNK. IL-1ß failed to induce COX-2 expression in cells transfected with siRNA for p65, p105, ERK1, or ERK2. Notably, NF-κB inhibitors reduced IL-1ß-induced ERK1/2 phosphorylation; however, the ERK1/2 inhibitor had no effect on the phosphorylation of the canonical NF-κB complex. Although transcription and translation inhibitors had no effect on IL-1ß-induced ERK1/2 phosphorylation, the silencing of canonical NF-κB complex in siRNA-transfected fibroblasts prevented IL-1ß-induced phosphorylation of ERK1/2. Taken together, our data indicate the importance of the non-transcriptional/translational activity of canonical NF-κB in the activation of ERK1/2 signaling involved in the IL-1ß-induced development of autoimmune diseases affecting the synovial tissue, such as RA.

MMP-3 activation is a hallmark indicating an early change in TMJ disorders, and is related to nitration.

Recent studies on temporomandibular joint (TMJ) disorders have suggested that matrix metalloproteinases (MMPs) are closely involved in the pathophysiological progression of the internal derangement (ID) of TMJ. The aim of this study was to investigate MMPs in synovial fluid (SF) at different stages of ID. To examine the relationship between MMP activation and ID progression, 54 SF samples from ID patients were classified based on the criteria of Wilkes and were assayed for MMP activity. It was found that MMP-3 activity was transiently increased in the intermediate stage. This increase in the active form of MMP-3 was also confirmed by Western blotting. When the 54 samples were classified into two groups based on the presence or absence of inflammatory findings, the intensity of MMP-3 activity correlated with the inflammatory symptoms. These findings suggest that MMP-3 activation is a hallmark of early degenerative changes in ID. The tylosin nitration by the peroxynitrite can regulate the enzyme activity. To elucidate the activating pathway of MMPs in vivo, nitrated proteins in SF were analysed by immunoprecipitation. Some nitrated proteins in SF were identified as MMP-2 and -3, and the nitration of MMP-3 rendered them active in vitro.

[Elevated serum aldolase activity in a patient of non-eosinophilic myofasciitis and synovitis with perifascicular atrophy].

A 35-year-old man suffered from myalgia and joint pain on walking for 5 months. Physical and neurological examinations revealed dermal sclerosis, skin swelling, redness of forearms, Raynaud's phenomenon, joint pain, myalgia and muscle weakness. Eosinophilia was not found and serum creatine kinase activity was normal, while aldolase was markedly elevated. Abnormal signals suggesting synovitis and myofasciitis were found on MRI images. Biopsy of the fascia of quadriceps femoris showed perivascular mononuclear cell infiltration. A muscle biopsy showed mononuclear cell infiltration mainly in the perimysium extending to the endmysium. Eosinophilic cells were not found, Perifascicular atrophy was observed. Corticosteroid therapy improved clinical symptoms and serum aldolase level. We diagnosed him as non-eosinophilic myofasciitis and synovitis with perifascicular atrophy. The serum aldolase activity is usuful for diagnosis and for monitoring the disease activity.

The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis.

Chronic inflammatory processes are based on a sustained and tightly regulated communication network among different cells types. This network comprises extracellular mediators such as cytokines, chemokines and matrix-degrading proteases, which orchestrate the participation of cells in the chronic inflammatory process. The mirrors of this outside communication world are intracellular transcription factor pathways, which shuttle information about inflammatory stimuli to the cell nucleus. This review examines the function of one key signal transduction pathway of inflammation--the p38 mitogen-activated protein kinases (p38MAPK). The signalling pathway is considered as crucial for the induction and maintenance of chronic inflammation, and its components thus emerge as interesting molecular targets of small molecule inhibitors for controlling inflammation. This review not only summarises the current knowledge of activation, regulation and function of the p38MAPK pathway but also examines the role of this pathway in clinical disease. It gives an overview of current evidence of p38MAPK activation in inflammatory arthritis and elaborates the key molecular determinants which contribute to p38MAPK activation in joint disease.

Curcumin alleviates rheumatoid arthritis-induced inflammation and synovial hyperplasia by targeting mTOR pathway in rats.

PURPOSE: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and symmetric polyarthritis. Mammalian target of rapamycin (mTOR) was reported to be a new target for RA therapy and its inhibitor rapamycin can significantly reduce the invasive force of fibroblast-like synoviocytes. Here, we determined the effect of curcumin to alleviate inflammation and synovial hyperplasia for the therapy of RA. MATERIALS AND METHODS: Collagen-induced arthritis (CIA) was developed in Wistar rats and used as a model resembling RA in humans. Rats were treated with curcumin (200 mg/kg) and the mTOR inhibitor rapamycin (2.5 mg/kg) daily for 3 weeks. Effects of the treatment on local joint, peripheral blood, and synovial hyperplasia in the pathogenesis of CIA were analyzed. RESULTS: Curcumin and rapamycin significantly inhibited the redness and swelling of ankles and joints in RA rats. Curcumin inhibited the CIA-induced mTOR pathway and the RA-induced infiltration of inflammatory cells into the synovium. Curcumin and rapamycin treatment inhibited the increased levels of proinflammatory cytokines including IL-1ß, TNF-α, MMP-1, and MMP-3 in CIA rats. CONCLUSION: Our findings show that curcumin alleviates CIA-induced inflammation, synovial hyperplasia, and the other main features involved in the pathogenesis of CIA via the mTOR pathway. These results provide evidence for the anti-arthritic properties of curcumin and corroborate its potential use for the treatment of RA.

The expression of collagenase 3 (MMP-13) mRNA in the synovial tissue is associated with histopathologic type II synovitis in rheumatoid arthritis.

The histopathologic analysis of the synovial tissue is important to distinguish rheumatoid arthritis (RA) from other forms of synovitis and to provide information about prognosis and therapeutic strategies at early stages of the disease. In this context, the present study was performed to investigate the correlation between immunohistopathological and morphological features of synovitis and the expression of collagenase 3 (MMP-13) known to contribute significantly to cartilage degradation in RA. In the histopathologic scoring system used in this study, type I synovitis is characterized by B lymphocyte infiltration and an intact lining, and is only mild destructive to cartilage and bone. Type II shows marked diffuse infiltrations of macrophages and T lymphocytes, an ulcerated lining, fibrin exudation, and invasive growth into cartilage and bone tissue. Investigating 36 patients with RA, 21 patients (58%) were positive for the expression of collagenase 3 mRNA in the synovial tissue. Among these patients, 19 showed a histopathologic type II synovitis and only 2 patients had undifferentiated synovitis. In contrast, synovial tissue samples from patients without collagenase 3 mRNA expression were characterized in 6 cases by type I, in 5 cases by type II and in 4 cases by undifferentiated synovitis. The analysis of the clinical data revealed that RA patients with a histopathologic type II synovitis and synovial tissue collagenase 3 mRNA expression had elevated levels of systemic markers of inflammation and received stronger therapies. The data suggest, that collagenase 3 expression and the histopathologic type II synovitis are associated with a severe and destructive course of RA.

Bilateral patellar dislocation associated with alpha-mannosidase deficiency.

Mannosidosis is an extremely rare genetic disease characterized by a deficiency of the lysosomal enzyme, alpha-mannosidase. This enzyme is necessary for cleavage of mannose from many glycoproteins. In the absence of this enzyme, mannose accumulates in cells throughout the body, including the joints and the synovium. This disease causes many skeletal changes including dysostosis multiplex, synovial hypertrophy, and Charcot-type joints. We report the case of a girl, aged 9 years and 6 months, who developed bilateral patellar dislocation and severe synovial hypertrophy secondary to alpha-mannosidase deficiency. Her disease was further complicated by Charcot elbow and bilateral hip and elbow avascular necrosis.

Immunoglobulin G from anti-glucose-6-phosphate isomerase antibodies positive patient with rheumatoid arthritis induces synovitis in cynomolgus monkeys.

Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) solely induce arthritis in mice. High titers of anti-GPI Abs are found in some patients with rheumatoid arthritis (RA), but their pathogenic role remains elusive. The aim of this study was to evaluate the pathogenic role of anti-GPI Abs in cynomolgus monkeys. IgG fractions were separated from sera of anti-GPI Abs-positive RA patients and healthy subjects and directly injected into the metacarpophalangeal joints of 4 cynomolgus monkeys. At day 16, the joints were harvested and examined histologically and immunohistochemically. The expression of C5a receptor (C5aR) molecule in the synovium was quantified by real-time PCR using cDNA from monkey joints. In monkey joints, IgG including anti-GPI Abs resulted in recruitment of granulocytes and mononuclear cells, strong deposition of human IgG on the articular surface, and overexpression of C5aR, but no joint swelling. No infiltrated cells or IgG deposition were observed in monkeys injected with IgGs from healthy subjects. Our results suggest that IgG fraction from RA patients including anti-GPI Abs may play a crucial role in the generation of synovitis in monkeys, although the pathogenesis of anti-GPI Abs in RA patients is still uncertain.

Preferential and non-selective cyclooxygenase inhibitors reduce inflammation during lipopolysaccharide-induced synovitis.

Synovitis in horses is frequently treated by administration of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase isoforms (COX-1 and COX-2). Constitutively expressed COX-1 is involved in physiologic functions such as maintenance of gastric mucosal integrity, whereas COX-2 is up-regulated at sites of inflammation. Thus, COX-2 inhibitors reduce inflammation with reduced gastrointestinal side effects as compared to non-selective COX inhibitors. The objective of the present study was to compare the anti-inflammatory effects of the preferential COX-2 inhibitor etodolac with the non-selective COX inhibitor phenylbutazone in horses with lipopolysaccharide (LPS)-induced synovitis. Three groups of horses (n=6) received no treatment, phenylbutazone (4.4 mg/kg, IV, q12h), or etodolac (23 mg/kg, IV, q12h), respectively, 2-h following injection of LPS into one middle carpal joint. Synovial fluid was analyzed for white blood cell (WBC) count, and TXB2 and PGE2 levels. Phenylbutazone and etodolac significantly reduced WBC count 6 and 24-h following injection of LPS compared to untreated horses. In addition, both drugs significantly reduced PGE2 levels (P<0.05) 6-h following LPS injection, whereas the probable COX-1 prostanoid TXB2 was significantly reduced by phenylbutazone (P<0.05), but not etodolac. Etodolac may serve as a more selective anti-inflammatory agent than phenylbutazone for treatment of equine synovitis.

Differential glucocorticoid metabolism in patients with persistent versus resolving inflammatory arthritis.

INTRODUCTION: Impairment in the ability of the inflamed synovium to generate cortisol has been proposed to be a factor in the persistence and severity of inflammatory arthritis. In the inflamed synovium, cortisol is generated from cortisone by the 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme. The objective of this study was to determine the role of endogenous glucocorticoid metabolism in the development of persistent inflammatory arthritis. METHODS: Urine samples were collected from patients with early arthritis (symptoms ≤12 weeks duration) whose final diagnostic outcomes were established after clinical follow-up and from patients with established rheumatoid arthritis (RA). All patients were free of disease-modifying anti-rheumatic drugs at the time of sample collection. Systemic measures of glucocorticoid metabolism were assessed in the urine samples by gas chromatography/mass spectrometry. Clinical data including CRP and ESR were also collected at baseline. RESULTS: Systemic measures of 11ß-HSD1 activity were significantly higher in patients with early arthritis whose disease went on to persist, and also in the subgroup of patients with persistent disease who developed RA, when compared with patients whose synovitis resolved over time. We observed a significant positive correlation between systemic 11ß-HSD1 activity and ESR/CRP in patients with established RA but not in any of the early arthritis patients group. CONCLUSIONS: The present study demonstrates that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11ß-HSD1 activity when compared with patients whose synovitis developed into RA or other forms of persistent arthritis. Low absolute levels of 11ß-HSD1 activity do not therefore appear to be a major contributor to the development of RA and it is possible that a high total body 11ß-HSD1 activity during early arthritis may reduce the probability of disease resolution.