glycogen and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identify commonality in muscle gene expression between this model and muscle from RA patients. Pain behaviour and locomotor activity were measured in a collagen-induced arthritis (CIA) model of RA (n = 9) and control (n = 9) rats. Energy substrates and metabolites, total alkaline-soluble protein:DNA ratio and mRNA abundance of 46 targeted genes were also determined in Extensor digitorum longus muscle. Expression of targeted mRNAs was quantified in Vastus Lateralis muscle from RA patients (n = 7) and healthy age-matched control volunteers (n = 6). CIA rats exhibited pain behaviour (p<0.01) and reduced activity (p<0.05) compared to controls. Muscle glycogen content was less (p<0.05) and muscle lactate content greater (p<0.01) in CIA rats. The bioinformatics analysis of muscle mRNA abundance differences from the control, predicted the activation of muscle protein metabolism and inhibition of muscle carbohydrate and fatty acid metabolism in CIA rats. Compared to age-matched control volunteers, RA patients exhibited altered muscle mRNA expression of 8 of the transcripts included as targets in the CIA model of RA. In conclusion, muscle energy metabolism and metabolic gene expression were altered in the CIA model, which was partly corroborated by targeted muscle mRNA measurements in RA patients. This research highlights the negative impact of RA on skeletal muscle metabolic homeostasis.

Topics: Aged; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Biomarkers; Disease Models, Animal; Female; Glycogen; Humans; Inflammation; Locomotion; Middle Aged; Muscle, Skeletal; Muscular Diseases; Myalgia; Rats; Rats, Inbred Lew; RNA, Messenger; Transcriptome

To investigate the role of glycogen metabolism in regulating rheumatoid fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and its underlying mechanism.. FLSs were separated from synovial tissues (STs) obtained from rheumatoid arthritis (RA) patients. Glycogen content was determined by periodic acid Schiff staining. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression of cytokines and matrix metalloproteinases (MMPs) was evaluated by quantitative real-time PCR. FLS proliferation was detected by EdU incorporation. Migration and invasion were measured by Boyden chamber assay.. Glycogen levels and glycogen synthase 1 (GYS1) expression were significantly increased in the ST and FLSs of RA patients. TNF-α or hypoxia induced GYS1 expression and glycogen synthesis in RA FLSs. GYS1 knockdown by shRNA decreased the expression of IL-1β, IL-6, CCL-2, MMP-1, and MMP-9 and proliferation and migration by increasing AMP-activated protein kinase (AMPK) activity in RA FLS. AMPK inhibitor or knockdown AMPK could reverse the inhibitory effect of GYS1 knockdown on the inflammatory response in RA FLSs; however, an AMPK agonist blocked RA FLS activity. We further determined that hypoxia-inducible factor-1α mediates TNF-α- or hypoxia-induced GYS1 expression and glycogen levels. Local joint depletion of GYS1 or intraperitoneal administration with an AMPK agonist ameliorated the severity of arthritis in rats with collagen-induced arthritis.. Our data demonstrate that GYS1-mediated glycogen accumulation contributes to FLS-mediated synovial inflammation in RA by blocking AMPK activation. In our knowledge, this is a first study linking glycogen metabolism to chronic inflammation. Inhibition of GYS1 might be a novel therapeutic strategy for chronic inflammatory arthritis, including RA.

Topics: Adult; Aged; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Arthritis, Rheumatoid; Biomarkers; Carbohydrate Metabolism; Cell Movement; Cell Proliferation; Cytokines; Female; Gene Expression; Gene Knockdown Techniques; Glycogen; Glycogen Synthase; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Inflammation Mediators; Male; Middle Aged; Ribonucleotides; Synovial Membrane; Synoviocytes

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints. High-fat diet (HFD) is a risk factor for RA and is related to inflammation but responds minimally to medication. Given the association between HFD and inflammation, it is important to understand the function of inflammation-related T cells in RA with HFD. Collagen-induced arthritis (CIA), a model of RA, was induced in HFD mice by injection of collagen II, and metabolic markers and T cells were analyzed. The metabolic index and IgG assay results were higher in HFD-CIA mice than in nonfat diet-CIA mice. Numbers of inflammation-related T cells and macrophages, such as Th1 and Th17 cells and M1 macrophages, were higher in spleens of HFD-CIA mice. HFD-CIA mice had a high level of α

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cell Differentiation; Collagen Type II; Diet, High-Fat; Genetic Vectors; Glycogen; Immunoglobulins; Interleukin-17; Lipid Metabolism; Male; Metabolic Diseases; Mice, Inbred DBA; Recombinant Proteins; Seminal Plasma Proteins; Spleen; T-Lymphocytes, Regulatory; Th17 Cells; Up-Regulation; Zn-Alpha-2-Glycoprotein

The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. CD4+ T cells comprise a large proportion of the inflammatory cells that invade the synovial tissue and may therefore be a cell type of pathogenic importance. Both methotrexate and infliximab are effective in the treatment of inflammatory arthritis; however, the biological effects triggered by these treatments and the biochemical mechanisms underlining the cell response are still not fully understood. Thus, in this study the global metabolic changes associated with methotrexate or infliximab treatment of isolated human CD4+ T cells were examined using gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. In total 148 metabolites involved in selective pathways were found to be significantly altered. Overall, the changes observed are likely to reflect the effort of CD4+ cells to increase the production of cellular reducing power to offset the cellular stress exerted by treatment. Importantly, analysis of the global metabolic changes associated with MTX or infliximab treatment of isolated human CD4+ T cells suggested that the toxicity associated with these agents is minimal when used at clinically relevant concentrations.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Arthritis, Rheumatoid; CD4-Positive T-Lymphocytes; Cells, Cultured; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Glycogen; Humans; Infliximab; Mass Spectrometry; Metabolome; Methotrexate; Tumor Necrosis Factor-alpha

The statement that blood in the articular cavity is cause of cartilage degradation is widely accepted as an axiom. Although the causes of the different articular diseases were explained in numerous studies, none of them has clarified the pathomechanism of haemarthrosis. Our aims were: 1/ to give a morphological description of the blood induced changes in the cartilage, 2/ to verify that the haemarthros is the cause of the cartilage degradation. 10 white rabbits were used in our experimental model. Artificial haemarthros was produced in their left hind knees by intraarticular injection of their own blood. The right hind served as control. The rabbits were divided into to five groups based on the time of the haemarthros (22-50 days). Samples of the condylar cartilage were taken for light, polarization, transmission and scanning electron microscopy examinations. Signs of the disorganization of the matrix structure were showed by polarisation microscope and serious lesions were detected in the perichondrium by scanning electron microscope. Similarity have been suggested amongst the pathomechanism of haemarthrosis and other degenerative cartilage diseases (e. g.: osteoarthrosis, rheumatoid arthritis), so we made the same comparison. In many cases similar morphological changes were observed, as described by other authors in case of degenerative diseases.

Topics: Animals; Arthritis, Rheumatoid; Cartilage Diseases; Cartilage, Articular; Cytoplasm; Disease Models, Animal; Extracellular Matrix; Glycogen; Glycosaminoglycans; Hemarthrosis; Hindlimb; Menisci, Tibial; Microscopy, Electron; Microscopy, Electron, Scanning; Microscopy, Polarization; Osteoarthritis; Porosity; Proteoglycans; Rabbits

A previous report described a cell isolate presumed to have arisen by accidental cocultivation (contamination) of the Chang 'liver' cell line and rheumatoid synovial cells. This cell isolate had the same glucose-6-phosphate dehydrogenase isoenzyme as the Chang cell and also some shared antigens. It clearly differed in its karyotype, its ability to grow in semisolid agar, and in the possession of bleb-like projections of the cytoplasmic membrane filled with collections of beaded or granular material. In addition, it had a novel antigen(s) not present in the Chang cell. As these properties might have been acquired from the synovial cells and because the bleb structures resembled those seen in some cell lines transformed by leucovirus the cell isolate has been further studied. Cytochemical methods at the light and electron microscope level showed that the granular material was polysaccharide in nature, probably glycogen. No evidence was found of the presence of a virus or a viral genome using a variety of techniques including attempted induction followed by 3H-uridine labelling of the cultures, and assay of the supernatant fluid from the culture for viral RNA-dependent DNA polymerase. In addition, cell extracts were not found to contain viral RNA-dependent DNA polymerase or RNA-dependent RNA polymerase. No rubella virus or leucovirus interspecies antigens were detected on the cell membranes.

Topics: Antigens, Viral; Arthritis, Rheumatoid; Cell Line; DNA Viruses; Genotype; Glycogen; Histocytochemistry; Hybrid Cells; Inclusion Bodies; Liver; Microscopy, Electron; Mycoplasma; Oncogenic Viruses; Polysaccharides; Protein Biosynthesis; RNA Viruses; Synovial Fluid; Transformation, Genetic

Electron microscope studies of the articular cartilages removed in the course of the operation on 6 patients with rheumatoid arthritis were carried out. The processes of destruction of chondrocytes and the cartilaginous matrix in different regions of the articular cartilage were traced. In the surface areas of the drastically changed cartilage there were observed leucocytes of the synovial fluid, and in deeper areas--disintegration of chondrocytes and extracellular disposition of lysosomes and altered organellas, destroyed cartilaginous cells. In these areas destruction of collagenous fibres was particularly intensive. In areas of the tissue remote from the destuction hypertrophy of chondrocytes due to hyperplasia of various organellas and the Golgi complex in particular were noted. In the Golgi zone granules of glycogen were detected. No mitoses were observed. Apparently, the enzymatic destruction of the cartilaginous matrix in rheumatoid arthritis could proceed at the expense of the activazation of the synovial fluid lysosomes and lysosomes of chondrocytes themselves. A reparative regeneration of the disintegrating matrix was realized mainly because of hypertrophy of the functionally preserved chondrocytes.

Topics: Arthritis, Rheumatoid; Cartilage, Articular; Cytoplasmic Granules; Endoplasmic Reticulum; Glycogen; Humans; Lysosomes; Mitochondrial Swelling; Neutrophils; Vacuoles

Topics: Acid Phosphatase; Adult; Aged; Arthritis, Rheumatoid; Female; Glycogen; Humans; Lymphocyte Activation; Lymphocytes; Male; Middle Aged

Topics: Arthritis, Rheumatoid; Cells, Cultured; Cytoplasmic Granules; Fibroblasts; Glycogen; Histocytochemistry; Humans; Inclusion Bodies; Inclusion Bodies, Viral; Lupus Erythematosus, Systemic; Microscopy, Electron; Polysaccharides; Skin; Staining and Labeling

Topics: Arthritis, Rheumatoid; Basophils; Blood Protein Electrophoresis; Glycogen; Humans; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Lupus Erythematosus, Systemic; Lymphocytes; Lymphocytosis; Neutrophils

Topics: Adult; Aged; Arthritis, Rheumatoid; Esterases; Female; Glycogen; Humans; Leukocytes; Lymphocytes; Male; Middle Aged; Phosphoric Monoester Hydrolases

The stained smears of the deposits from one pericardial and 19 pleural effusions complicating rheumatoid arthritis were examined. On the basis of clinical and biochemical evidence it was considered that in six cases the effusions were due to the rheumatoid disease while in a further nine cases the association was considered likely. In the remaining five cases the association was considered to be due to chance as other causes for the effusions were diagnosed. On cytological examination, seven cases showed a characteristic picture of degenerating polymorphs with amorphous extracellular material and epithelioid cells many of which were multinucleate. Five others contained similar amorphous material without epithelioid cells; of these two had many plasma cells and a third numerous macrophages probably containing ;droplets' of rheumatoid factor complex. Thus in 12 of 15 cases a definite diagnosis of rheumatoid effusion could be made. In the remaining five cases cytological examination confirmed that the effusions were unrelated to the rheumatoid disease.The extracellular material gave a non-specific fluorescence with labelled anti-gamma globulin antisera, and since this reaction was not seen in control pleural fluid deposits, or with preparations of fibrin, it may have a confirmatory value. It is concluded that in many cases reliable cytological evidence can be found to confirm or refute a diagnosis of rheumatoid pleural or pericardial effusion. This may be helpful in the management of the rheumatoid disease.

Topics: Adult; Aged; Arthritis, Rheumatoid; Cytodiagnosis; Cytoplasm; Female; Fluorescent Antibody Technique; Glycogen; Humans; Immunoglobulins; Lymphocytes; Macrophages; Male; Microscopy, Electron; Middle Aged; Pericardial Effusion; Pinocytosis; Pleural Effusion; Precipitin Tests; Pseudopodia; Staining and Labeling

Topics: Arthritis, Rheumatoid; Cytoplasmic Granules; Glycogen; Humans; Leukocytes; Microscopy, Electron; Synovial Fluid

Recent experimental evidence suggests that hydrocortisone (Kendall's Compound F) is probably the principal glycogenic steroid secreted by the adrenal cortex and that under conditions of stress it may participate more than cortisone in physiologic reactions. Laboratory studies indicate that hydrocortisone has greater physiologic activity, milligram for milligram, than cortisone and with certain assays its potency is twice as great.Two forms of hydrocortisone, the free alcohol preparation and the acetate, were given systemically to patients with rheumatoid arthritis and were observed to possess significant differences in ability to suppress the disease manifestations. When administered orally in large initial doses, hydrocortisone (free alcohol) appeared to produce greater suppressive effects, milligram for milligram, than either hydrocortisone acetate or cortisone acetate. Comparisons of potency made by determining maintenance dosage requirements for equivalent degrees of clinical control in the same patients indicated that the effectiveness of hydrocortisone (free alcohol) is more than 50 per cent greater than that of either the free or acetated forms of cortisone and approximately twice as great as that of hydrocortisone acetate. Certain observations suggested that the greater antirheumatic activity of hydrocortisone (free alcohol) is not accompanied by a correspondingly greater tendency toward endocrine complications. If more extensive future investigations support this observation, hydrocortisone (free alcohol), by producing equally efficient results with smaller doses, may prove superior to cortisone as a therapeutic agent.Intra-articular injections of hydrocortisone acetate appear to have only a limited place in the management of rheumatoid arthritis but may be used for temporary relief under certain conditions. In preliminary studies by the author it was noted that whereas improvement resulted in 80 per cent of the treated joints, the improvement was graded as pronounced or very pronounced in only one-half of the joints so injected. In almost all instances the benefits derived were quite temporary. Results observed in treatment of osteoarthritic joints by this method were decidedly poorer than in rheumatoid arthritis.

Topics: Adrenal Cortex; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Assay; Biological Transport; Cortisone; Ethanol; Glycogen; Humans; Hydrocortisone; Mental Disorders