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ID PMID Title PublicationDate abstract
26360112 Chemical Proteomic Platform To Identify Citrullinated Proteins. 2015 Nov 20 Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and are routinely used for disease diagnosis. Protein citrullination is also increased in cancer and other autoimmune disorders, suggesting that citrullinated proteins may serve as biomarkers for diseases beyond RA. To identify these citrullinated proteins, we developed biotin-conjugated phenylglyoxal (biotin-PG). Using this probe and our platform technology, we identified >50 intracellular citrullinated proteins. More than 20 of these are involved in RNA splicing, suggesting, for the first time, that citrullination modulates RNA biology. Overall, this chemical proteomic platform will play a key role in furthering our understanding of protein citrullination in rheumatoid arthritis and potentially a wider spectrum of inflammatory diseases.
26807908 Low Serum 25-Hydroxyvitamin D Levels Are Associated with Dry Eye Syndrome. 2016 BACKGROUND: Dry eye syndrome (DES) is a common tear film and ocular surface disease that results in discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. Systemic diseases associated with DES include diabetes mellitus, rheumatoid arthritis, depression, anxiety, thyroid disease, allergic diseases, irritable bowel syndrome, chronic pain syndrome, and hyperlipidemia. Interestingly, it has been found that most of these are associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) or inadequate sunlight exposure. METHODS: In this cross-sectional data analysis, noninstitutionalized adults aged ≥19 years (N = 17,542) who participated in Korean National Health and Nutrition Examination Survey 2010-2012 were included. Information regarding duration of sunlight exposure was collected from the survey participants. Serum 25(OH)D and zinc levels were measured. The confounding variables were age, gender, sunlight exposure time, region of residence, obesity, serum 25(OH)D level, diabetes mellitus, rheumatoid arthritis, depression, thyroid disorder, atopic dermatitis, history of ocular surgery, regular exercise, and walking exercise. RESULTS: Mean serum 25(OH)D levels of subjects with and without DES were 16.90 ± 6.0 and 17.52 ± 6.07 (p<0.001). Inadequate sunlight exposure time (odds ratio [OR], 1.554; 95% confidence interval [CI], 1.307-1.848), urban residence (OR, 1.669; 95% CI, 1.456-1.913), indoor occupation (OR, 1.578; 95% CI, 1.389-1.814), and low serum 25(OH)D level (OR, 1.158; 95% CI, 1.026-1.308) were the risk factors for DES. After adjusting for age, sex, obesity, diabetes mellitus, rheumatoid arthritis, depression, thyroid disorder, atopic dermatitis, history of ocular surgery, regular exercise, and occupation, low serum 25(OH)D level (OR, 1.178; 95% CI, 1.010-1.372) and deficient sunlight exposure time (OR, 1.383; 95% CI, 1.094-1.749) were the risk factors for diagnosed DES. CONCLUSION: Low serum 25(OH)D levels and inadequate sunlight exposure are associated with DES in Korean adults. These results suggest that sufficient sunlight exposure or vitamin D supplementation may be useful in DES treatment.
26699442 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia 2015 Nov An Expert Panel convened by the National Lipid Association previously developed a consensus set of recommendations for the patient-centered management of dyslipidemia in clinical medicine (part 1). These were guided by the principle that reducing elevated levels of atherogenic cholesterol (non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) reduces the risk for atherosclerotic cardiovascular disease. This document represents a continuation of the National Lipid Association recommendations developed by a diverse panel of experts who examined the evidence base and provided recommendations regarding the following topics: (1) lifestyle therapies; (2) groups with special considerations, including children and adolescents, women, older patients, certain ethnic and racial groups, patients infected with human immunodeficiency virus, patients with rheumatoid arthritis, and patients with residual risk despite statin and lifestyle therapies; and (3) strategies to improve patient outcomes by increasing adherence and using team-based collaborative care.
26168766 High fracture probability predicts fractures in a 4-year follow-up in women from the RAC-O 2015 Dec In 770 postmenopausal women, the fracture incidence during a 4-year follow-up was analyzed in relation to the fracture probability (FRAX risk assessment tool) and risk (Garvan risk calculator) predicted at baseline. Incident fractures occurred in 62 subjects with a higher prevalence in high-risk subgroups. Prior fracture, rheumatoid arthritis, femoral neck T-score and falls increased independent of fracture incidence. INTRODUCTION: The aim of the study was to analyze the incidence of fractures during a 4-year follow-up in relation to the baseline fracture probability and risk. METHODS: Enrolled in the study were 770 postmenopausal women with a mean age of 65.7 ± 7.3 years. Bone mineral density (BMD) at the proximal femur, clinical data, and fracture probability using the FRAX tool and risk using the Garvan calculator were determined. Each subject was asked yearly by phone call about the incidence of fracture during the follow-up period. RESULTS: Of the 770 women, 62 had a fracture during follow-up, and 46 had a major fracture. At baseline, BMD was significantly lower, and fracture probability and fracture risk were significantly higher in women who had a fracture. Among women with a major fracture, the percentage with a high baseline fracture probability (>10 %) was significantly higher than among those without a fracture (p < 0.01). Fracture incidence during follow-up was significantly higher among women with a high baseline fracture probability (12.7 % vs. 5.2 %) and a high fracture risk (9.2 vs. 5.3 %) so that the "fracture-free survival" curves were significantly different (p < 0.05). The number of clinical risk factors noted at baseline was significantly associated with fracture incidence (chi-squared = 20.82, p < 0.01). Prior fracture, rheumatoid arthritis, and femoral neck T-score were identified as significant risk factors for major fractures (for any fractures, the influence of falls was also significant). CONCLUSIONS: During follow-up, fracture incidence was predicted by baseline fracture probability (FRAX risk assessment tool) and risk (Garvan risk calculator). A number of clinical risk factors and a prior fracture, rheumatoid arthritis, femoral neck T-score, and falls were independently associated with an increased incidence of fractures. [Corrected]
26213636 STAT1 is Constitutively Activated in the T/C28a2 Immortalized Juvenile Human Chondrocyte L 2015 Apr T/C28a2 immortalized juvenile human chondrocytes were employed to determine the extent to which activation of Signal Transducers and Activators of Transcription-1 (STAT1) occurred in response to recombinant human interleukin-6 (rhIL-6) or rhIL-6 in combination with the soluble IL-6 receptor (sIL-6R). Two forms of STAT1, STAT1A and STAT1B, were identified on SDS-PAGE and western blotting with anti-STAT1 antibody. Western blotting revealed that STAT1 was constitutively phosphorylated (p-STAT1). Although incubation of T/C28a2 chondrocytes with rhIL-6 (50 ng/ml) increased p-STAT1A by Δ=22.3% after 30 min, this percent difference failed to reach significance by Chi-square analysis. Similarly, no effect of rhIL-6 (Δ=+10.7%) on p-STAT1B was seen at 30 min. In contrast, although the combination of rhIL-6 plus sIL-6R had no effect on p-STAT1A, rhIL-6 plus sIL-6R increased p-STAT1B by Δ=73.3% (p<0.0001) after 30 min compared to the control group and by Δ=56.7% (p<0.0001) compared to rhIL-6 alone. Janex-1, a Janus kinase-3-specific inhibitor (100 μM) partially reduced the effect of rhIL-6 on p-STAT1B by Δ=27.7% (p<0.05). The results of this study showed that STAT1A/STAT1B was constitutively activated in T/C28a2 chondrocytes. Although rhIL-6 increased p-STAT1B to a small extent, the combination of rhIL-6 plus sIL-6R was far more effective in stimulating STAT1B phosphorylation compared to controls or rhIL-6 alone. These data support the likelihood that although JAK3-mediated activation of STAT1 in T/C28a2 chondrocytes may involve the IL-6/IL-6R/gp130 pathway, these results indicated that STAT1 activation in response to IL-6 preferentially involved IL-6 trans-signaling via sIL-6R.
26982203 Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation. 2016 Oct OBJECTIVES: Inflammation in diseases such as rheumatoid arthritis (RA) stimulates osteoclast-mediated articular bone erosion and inhibits osteoblast-mediated bone formation, leading to a net loss of bone. Pro-inflammatory cytokines and antagonists of the Wnt signalling pathway have been implicated in the inhibition of osteoblast differentiation and activity in RA, contributing to the erosive process and impairing erosion healing. Importantly, osteoblast differentiation and function are also regulated by the osteogenic bone morphogenetic protein (BMP) signalling pathway, which is antagonized by BMP3. We therefore examined the potential role of BMP3 in inflammatory arthritis. METHOD: Two murine models of RA, K/BxN serum transfer arthritis (STA) and antigen-induced arthritis (AIA), were used to establish the temporal expression of BMP3 and the cellular sources of BMP3 mRNA and protein in inflammatory arthritis. To determine the effects of inflammation on the expression of BMP3 in osteoblasts, murine calvarial osteoblasts were treated with pro-inflammatory cytokines and BMP3 expression was assessed. RESULTS: In both murine models of RA, BMP3 mRNA and protein are highly expressed by osteoblasts lining inflammation-bone interfaces late in the course of arthritis. Synovial tissues are not a significant source of BMP3. BMP3 expression is induced in osteocalcin-expressing osteoblasts in vitro following stimulation by tumour necrosis factor (TNF). CONCLUSIONS: These data implicate BMP3 as a novel factor that may act locally to contribute to the erosive process and inhibit the repair of articular bone in RA through inhibition of osteoblast differentiation and function.
25870945 Oxidative state and oxidative metabolism in the brain of rats with adjuvant-induced arthri 2015 Jun The purpose of the present study was to evaluate the oxidative status of the brain of arthritic rats, based mainly on the observation that arthritis induces a pronounced oxidative stress in the liver of arthritis rats and that morphological alterations have been reported to occur in patients with rheumatoid arthritis. Rats with adjuvant-induced arthritis were used. These animals presented higher levels of reactive oxygen species (ROS) in the total brain homogenate (25% higher) and in the mitochondria (+55%) when compared to healthy rats. The nitrite plus nitrate contents, nitric oxide (NO) markers, were also increased in both mitochondria (+27%) and cytosol (+14%). Arthritic rats also presented higher levels of protein carbonyl groups in the total homogenate (+43%), mitochondria (+69%) and cytosol (+145%). Arthritis caused a diminution of oxygen consumption in isolated brain mitochondria only when ascorbate was the electron donor. The disease diminished the mitochondrial cytochrome c oxidase activity by 55%, but increased the transmembrane potential by 16%. The pro-oxidant enzyme xanthine oxidase was 150%, 110% and 283% higher, respectively, in the brain homogenate, mitochondria and cytosol of arthritic animals. The same occurred with the calcium-independent NO-synthase activity that was higher in the brain homogenate (90%) and cytosol (122%) of arthritic rats. The catalase activity, on the other hand, was diminished by arthritis in all cellular fractions (between 30 and 40%). It is apparent that the brain of rats with adjuvant-induced arthritis presents a pronounced oxidative stress and a significant injury to lipids and proteins, a situation that possibly contributes to the brain symptoms of the arthritis disease.
27749230 Characterisation of peripheral blood mononuclear cell microRNA in early onset psoriatic ar 2017 Jan OBJECTIVES: To evaluate the micro-RNA (miRNA) expression profile in patients with early psoriatic arthritis (PsA) in order to assess the role of miRNAs as potential PsA biomarkers. METHODS: The expression of 723 mature miRNAs in peripheral blood mononuclear cells of early PsA patients in comparison with early-rheumatoid arthritis (ERA) patients and healthy controls (HC) was evaluated using a miRNA microarray. All patients had active disease and were naïve from treatment. The results were validated for a specific miRNA (miR-21-5p) in the entire series of patients plus an additional group of early PsA, ERA and HC using droplet digital PCR. RESULTS: In PsA, microarray analysis revealed a distinct pattern of 19 (vs. HC) and 48 (vs. ERA) deregulated miRNAs (p<0.05). The significant up-regulation of miR-21-5p both in early PsA and in ERA in comparison with HC was validated and confirmed. In PsA, miR-21-5p was found significantly down regulated after 12 weeks of therapy, which significantly correlated with the reduction of DAPSA score. CONCLUSIONS: In early PsA, a 19- (vs. HC) and 48- (vs. ERA) miRNA signature was identified. A differential expression of miRNAs in patients with active disease makes them attractive biomarkers of psoriatic disease. MiR-21-5p was found up-regulated both in early PsA and ERA, a finding which highlights its role in the inflammatory process in general and its potential role as a therapeutic target in different inflammatory disorders. A potential role of miR-21-5p as a response to treatment biomarker in early PsA has been identified.
26704941 Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis. 2016 Feb Progressive cartilage destruction, mediated by invasive fibroblast-like synoviocytes, is a central feature in the pathogenesis of rheumatoid arthritis (RA). Members of the Snail family of transcription factors are required for cell migration and invasion, but their role in joint destruction remains unknown. Herein, we demonstrate that Snail is essential for the formation of extracellular matrix-degrading invadosomal structures by synovial cells from collagen-induced arthritis (CIA) rats and RA patients. Mechanistically, Snail induces extracellular matrix degradation in synovial cells by repressing PTEN, resulting in increased phosphorylation of platelet-derived growth factor receptor and activation of the phosphatidylinositol 3-kinase/AKT pathway. Of significance, Snail is overexpressed in synovial cells and tissues of CIA rats and RA patients, whereas knockdown of Snail in CIA joints prevents cartilage invasion and joint damage. Furthermore, Snail expression is associated with an epithelial-mesenchymal transition gene signature characteristic of transglutaminase 2/transforming growth factor-β activation. Transforming growth factor-β and transglutaminase 2 stimulate Snail-dependent invadosome formation in rat and human synoviocytes. Our results identify the Snail-PTEN platelet-derived growth factor receptor/phosphatidylinositol 3-kinase axis as a novel regulator of the prodestructive invadosome-forming phenotype of synovial cells. New therapies for RA target inflammation, and are only partly effective in preventing joint damage. Blocking Snail and/or its associated gene expression program may provide an additional tool to improve the efficacy of treatments to prevent joint destruction.
26860973 A herbal formula comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos, attenu 2016 Feb 10 RL, a traditional remedy for Rheumatoid arthritis (RA), comprises two edible herbs, Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. We have reported that RL could inhibit the production of inflammatory mediators in immune cells. Here we investigated the effects and the mechanism of action of RL in collagen-induced arthritis (CIA) rats. RL significantly increased food intake and weight gain of CIA rats without any observable adverse effect; ameliorated joint erythema and swelling; inhibited immune cell infiltration, bone erosion and osteophyte formation in joints; reduced joint protein expression levels of TLR4, phospho-TAK1, phospho-NF-κB p65, phospho-c-Jun and phospho-IRF3; lowered levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-17A and MCP-1 in sera and TNF-α, IL-6, IL-1β and IL-17A in joints); elevated serum IL-10 level; reinvigorated activities of antioxidant SOD, CAT and GSH-Px in the liver and serum; reduced Th17 cell proportions in splenocytes; inhibited splenocyte proliferation and activation; and lowered serum IgG level. In conclusion, RL at nontoxic doses inhibited TLR4 signaling and potently improved clinical conditions of CIA rats. These findings provide further pharmacological justifications for the traditional use of RL in RA management.
25605261 Therapeutic effect of Cryptotanshinone on collagen-induced arthritis in rats via inhibitin 2015 Jun The discovery of new therapeutic drugs with the ability of preventing inflammation and joint destruction with less adverse effects is extremely urgent for rheumatoid arthritis (RA). Cryptotanshinone (CTS), an active component isolated from the root of Salvia miltiorrhiza Bunge, has been reported to have antibacterial and antitumor effects. However, its effects on RA have not been clearly elucidated. Here, we investigated the therapeutic effect of CTS on type II collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms. Our results revealed that CTS treatment efficaciously ameliorated inflammation and joint destruction of rats with CIA. Both in vivo and in vitro studies showed that CTS suppressed the production of proinflammatory cytokines including interleukin 1β, tumor necrosis factor alpha, and interleukin 17α production and downregulated the production and activity of matrix metalloproteinase 9. By receptor activator of nuclear factor kappa B (NF-κB) ligand-induced bone marrow macrophages, we observed that CTS could inhibit osteoclast differentiation, which is critic for joint destruction. Further studies on inflammatory signaling revealed that CTS could inhibit the degradation of inhibitor of NF-κB (IκB) α in vivo and in vitro, prevent the nuclear translocation of NF-κB p65 induced by lipopolysaccharide in a time- and dose-dependent manner. By electrophoretic mobility shift assay and luciferase reporter assay, we found that CTS distinctively inhibited the NF-κB DNA binding activity and NF-κB-dependent luciferase activity. These results indicate that the therapeutic effect of CTS on CIA is accomplished mainly through the inhibition of NF-κB signaling. Our findings provide the evidence to develop CTS as a potential therapeutic agent for patients with RA.
27320934 [Clinical utility of the liposteroid therapy: Potential effects on the macrophage activati 2016 Liposteroid, a lipid emulsion containing dexamethasone, was developed in Japan. This drug is effective against rheumatoid arthritis, and has fewer side effects than dexamethasone. Moreover, at high dosage, liposteroid has been effectively used for the treatment of macrophage activation syndrome, because the lipid emulsions are easily taken up by phagocytes, and are retained in macrophages. Its anti-inflammatory effect was found to be 2-5 times higher than that of dexamethasone in arthritis and granuloma rat models. Japanese researchers have reported the clinical efficacy and utility of liposteroid in the treatment of diseases with macrophage activation. These include hemophagocytic lymphohistiocytosis, graft-versus-host disease, and pulmonary hemosiderosis. Here, we describe the clinical effects of liposteroid on macrophage activation syndrome and the hypothalamus-pituitary-adrenal axis in patients.
27437696 Secukinumab: a promising therapeutic option in spondyloarthritis. 2016 Sep Psoriatic arthritis (PsA) is the second most common chronic inflammatory joint disease. Ankylosing spondylitis (AS) is another less common but equally chronic and disabling spondyloarthritis (SpA). Therapeutic agents for the treatment of these diseases have been somewhat lacking as compared with those available for rheumatoid arthritis, which represents a significant challenge for both the treating physician and the pharmaceutical industry. A promising development for our understanding of the physiopathology of PsA and AS involves new targets to interrupt IL-17 and IL-12/IL-23 pathways. Up to 30-40 % of SpA patients have inadequate or poor response, or are intolerant to anti-TNF therapies. Therefore, there has been a clear unmet medical need in an important group of these patients. As a result, new therapeutic targets have emerged for the treatment of both axial and peripheral SpA. Interleukin 17 (IL-17) is a pro-inflammatory cytokine that is increased in psoriatic lesions as well as in the synovial fluid of patients with PsA and in sites of enthesitis in SpA. IL-23 has been shown to play an important role in the polarization of CD4+ T-cells to become IL-17 producers. Based on these evidences, blockade of the cytokine IL-17 or its receptors was considered to have therapeutic implications for the treatment of psoriasis, as well as PsA and AS.This article presents a thorough review of an IL-17 A blocking agent, its mechanism of action, its clinical efficacy and its therapeutic safety.
26120598 Suppression of experimental arthritis through AMP-activated protein kinase activation and 2015 Feb 28 Autophagy plays a central role in various disease processes. However, its contribution to inflammatory arthritides such as rheumatoid arthritis (RA) is unclear. We observed that autophagy is engaged in the K/BxN serum transfer model of RA but autophagic flux is severely impaired. Metformin is an anti-diabetic drug that has been shown to stimulate autophagy. Induction of autophagic flux, through metformin-mediated AMP-activated protein kinase (AMPK) activation and interruption of mammalian target of rapamycin (mTOR) signaling mitigated the inflammation in experimental arthritis. Further investigation into the effects of metformin suggest that the drug directly activates AMPK and dose-dependently suppressed the release of TNF-α, IL-6, and MCP-1 by macrophages while enhancing the release of IL-10 in vitro. In vivo, metformin treatment significantly suppressed clinical arthritis and inflammatory cytokine production. Mechanistic studies suggest that metformin exerts its anti-inflammatory effects by correcting the impaired autophagic flux observed in the K/BxN arthritis model and suppressing NF-κB-mediated signaling through selective degradation of IκB kinase (IKK). These findings establish a central role for autophagy in inflammatory arthritis and argue that autophagy modulators such as metformin may represent potential therapeutic agents for the treatment of RA.
25636414 Aiming for a simpler early arthritis MRI protocol: can Gd contrast administration be elimi 2015 May PURPOSE: To evaluate whether intravenous gadolinium (Gd) contrast administration can be eliminated when evaluating synovitis and tenosynovitis in early arthritis patients, thereby decreasing imaging time, cost, and invasiveness. MATERIALS AND METHODS: Wrist MRIs of 93 early arthritis patients were evaluated by two readers for synovitis of the radioulnar, radiocarpal, and intercarpal joints, according to the Rheumatoid Arthritis MRI Scoring method (RAMRIS), and for tenosynovitis in ten compartments. Scores of MRI images without Gd contrast enhancement were compared to scores obtained when evaluating all, including contrast-enhanced, MRI images as reference. Subsequently, a literature review and pooled analysis of data from the present and two previous studies were performed. RESULTS: At the individual joint/tendon level, sensitivity to detect synovitis without Gd contrast was 91 % and 72 % for the two readers, respectively, with a specificity of 51 % and 81 %. For tenosynovitis, the sensitivity was 67 % and 54 %, respectively, with a specificity of 87 % and 91 %. Pooled data analysis revealed an overall sensitivity of 81 % and specificity of 50 % for evaluation of synovitis. Variations in tenosynovitis scoring systems hindered pooled analyses. CONCLUSION: Eliminating Gd contrast administration resulted in low specificity for synovitis and low sensitivity for tenosynovitis, indicating that Gd contrast administration remains essential for an optimal assessment. KEY POINTS: • Eliminating gadolinium contrast administration results in low specificity for synovitis • For tenosynovitis, sensitivity is low without gadolinium contrast administration • Gadolinium contrast administration remains essential for evaluating synovitis and tenosynovitis in early arthritis.
27461230 From the Medical Board of the National Psoriasis Foundation: Perioperative management of s 2016 Oct Treatment with systemic immunomodulatory agents is indicated for patients with moderate to severe plaque psoriasis and psoriatic arthritis. In these patients, surgery may confer an increased risk of infectious or surgical complications. We conducted a literature review to examine studies addressing the use of methotrexate, cyclosporine, and targeted immunomodulatory agents (tumor necrosis factor-alfa inhibitors, interleukin [IL]-12/23 inhibitors, IL-17 inhibitors) in patients undergoing surgery. We examined 46 total studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. One study in patients with psoriasis and psoriatic arthritis reviewed 77 procedures and did not find an elevated risk of postoperative complications with tumor necrosis factor-alfa and IL-12/23 inhibitors even with major surgeries. Based on level III evidence, infliximab, adalimumab, etanercept, methotrexate, and cyclosporine can be safely continued through low-risk operations in patients with psoriasis and psoriatic arthritis. For moderate- and high-risk surgeries, a case-by-case approach should be taken based on the patient's individual risk factors and comorbidities.
25853338 Treatment of Collagen-Induced Arthritis Using Immune Modulatory Properties of Human Mesenc 2016 Mesenchymal stem cells (MSCs) have immune modulatory properties. We investigated the potential therapeutic effects of human bone marrow (BM)-, adipose tissue (AD)-, and cord blood (CB)-derived MSCs in an experimental animal model of rheumatoid arthritis (RA) and explored the mechanism underlying immune modulation by MSCs. We evaluated the therapeutic effect of clinically available human BM-, AD-, and CB-derived MSCs in DBA/1 mice with collagen-induced arthritis (CIA). CIA mice were injected intraperitoneally with three types of MSCs. Treatment control animals were injected with 35 mg/kg methotrexate (MTX) twice weekly. Clinical activity in CIA mice, degree of inflammation, cytokine expression in the joint, serum cytokine levels, and regulatory T cells (Tregs) were evaluated. Mice treated with human BM-, AD-, and CB-MSCs showed significant improvement in clinical joint score, comparable to MTX-treated mice. Histologic examination showed greatly reduced joint inflammation and damage in MSC-treated mice compared with untreated mice. Microcomputed tomography also showed little joint damage in the MSC-treated group. MSCs significantly decreased serum interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon-γ and increased IL-10 and transforming growth factor-β levels. Tregs were increased in mice treated with MSCs compared to untreated or MTX-treated mice. Human BM-, AD-, and CB-MSCs significantly suppressed joint inflammation in CIA mice. The cells decreased proinflammatory cytokines and upregulated anti-inflammatory cytokines and induced Tregs. Therefore, our study suggests that the use of human BM-, AD-, and CB-MSCs could be an effective therapeutic approach for RA.
26085099 Porphyromonas gingivalis Stimulates Bone Resorption by Enhancing RANKL (Receptor Activator 2015 Aug 14 Periodontitis has been associated with rheumatoid arthritis. In experimental arthritis, concomitant periodontitis caused by oral infection with Porphyromonas gingivalis enhances articular bone loss. The aim of this study was to investigate how lipopolysaccharide (LPS) from P. gingivalis stimulates bone resorption. The effects by LPS P. gingivalis and four other TLR2 ligands on bone resorption, osteoclast formation, and gene expression in wild type and Tlr2-deficient mice were assessed in ex vivo cultures of mouse parietal bones and in an in vivo model in which TLR2 agonists were injected subcutaneously over the skull bones. LPS P. gingivalis stimulated mineral release and matrix degradation in the parietal bone organ cultures by increasing differentiation and formation of mature osteoclasts, a response dependent on increased RANKL (receptor activator of NF-κB ligand). LPS P. gingivalis stimulated RANKL in parietal osteoblasts dependent on the presence of TLR2 and through a MyD88 and NF-κB-mediated mechanism. Similarly, the TLR2 agonists HKLM, FSL1, Pam2, and Pam3 stimulated RANKL in osteoblasts and parietal bone resorption. LPS P. gingivalis and Pam2 robustly enhanced osteoclast formation in periosteal/endosteal cell cultures by increasing RANKL. LPS P. gingivalis and Pam2 also up-regulated RANKL and osteoclastic genes in vivo, resulting in an increased number of periosteal osteoclasts and immense bone loss in wild type mice but not in Tlr2-deficient mice. These data demonstrate that LPS P. gingivalis stimulates periosteal osteoclast formation and bone resorption by stimulating RANKL in osteoblasts via TLR2. This effect might be important for periodontal bone loss and for the enhanced bone loss seen in rheumatoid arthritis patients with concomitant periodontal disease.
28090451 Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease. 2016 Dec Early detection of musculoskeletal disease leads to improved therapies and patient outcomes, and would benefit greatly from imaging at the cellular and molecular level. As it becomes clear that assessment of multiple tissues and functional processes are often necessary to study the complex pathogenesis of musculoskeletal disorders, the role of multi-modality molecular imaging becomes increasingly important. New positron emission tomography-magnetic resonance imaging (PET-MRI) systems offer to combine high-resolution MRI with simultaneous molecular information from PET to study the multifaceted processes involved in numerous musculoskeletal disorders. In this article, we aim to outline the potential clinical utility of hybrid PET-MRI to these non-oncologic musculoskeletal diseases. We summarize current applications of PET molecular imaging in osteoarthritis (OA), rheumatoid arthritis (RA), metabolic bone diseases and neuropathic peripheral pain. Advanced MRI approaches that reveal biochemical and functional information offer complementary assessment in soft tissues. Additionally, we discuss technical considerations for hybrid PET-MR imaging including MR attenuation correction, workflow, radiation dose, and quantification.
27552385 Comparative Long-Term Evaluation of Patients With Juvenile Inflammatory Myopathies. 2016 Sep OBJECTIVES: We conducted a retrospective study analyzing the clinical features, laboratory findings, demographics, and long-term prognoses of patients with juvenile inflammatory myopathies to determine possible predictors indicating the use of aggressive immunotherapy and the response to and complications of treatment. METHODS: The medical records of 41 patients with juvenile inflammatory myopathies seen at University of Tennessee-affiliated hospitals in Memphis from 1969 to 2008 were evaluated. Patients' clinical characteristics, laboratory studies, muscle biopsies, and electromyography were reviewed. All patients were treated with prednisone initially; additionally, 14 patients received varying combinations of other immunosuppressant therapies. RESULTS: Seventy-three percent of the patients experienced remission. Patients in the group that did not go into remission had specific characteristics at onset: they were comparatively older and had more severe rashes, contractures, arthritis, and systemic involvement. Also, patients with positive autoantibodies (antinuclear antibody, rheumatoid arthritis factor) had better outcomes. CONCLUSIONS: Juvenile inflammatory myopathies have relatively good prognoses. Initial presentation at advanced age or with severe rash, systemic vasculopathies, anemia, or arthritis portends refractory disease; in these patients, second- and third-line therapies improve outcome.