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Abstracts

Presentations at the annual meeting of the Finnish Society for Rheumatology, Tampere, 28–29 January 2010

Pages 442-446 | Published online: 11 Oct 2010
 

SCLEREDEMA ADULTORUM OF BUSCHKE: A CASE REPORT AND REVIEW OF THE LITERATURE

O Marjoniemi, O Kaipiainen-Seppänen

Department of Medicine, Kuopio University Hospital, Kuopio, Finland

Objectives: To describe type 3 scleredema adultorum.

Methods: Search of Medline (PubMed) was performed using the words ‘Scleredema adultorum’. Scleredema adultorum is a rare skin metabolic disorder characterized by hardening and thickening of the skin, typically over the face, neck, shoulders, and upper back, but not over the hands or feet. Scleredema is also known as scleredema diabeticorum and scleroderma diabeticorum of Buschke, after the German dermatologist Abraham Buschke (1868–1943) who first described it. Three types of scleredema adultorum have been described: Type 1 is usually preceded by a febrile episode (often a strep throat) in younger people, females more often than males, and may involve other organs (tongue, oesophagus, heart) aside from the skin. About half of these cases resolve spontaneously within 2 years. Type 2 is associated with paraproteinaemias including multiple myeloma. Type 3 is associated with diabetes mellitus (DM): scler (hard) + oedema (swelling). It is a metabolic disorder in which water and mucin are increased between dermal collagen fibres. Massive amounts of acid mucopolysaccharides are deposited in the dermis; the most typical materials are hyaluronic acid and less sulfated glycosaminoglycans.

Case report: A 58-year-old woman with a history of high blood pressure, type I DM, MCC, dyslipoproteinaemia, arthralgia, neuropathy, and retinopathy was examined. She had difficult-to-control insulin-dependent DM, non-pitting induration of the skin (posterior neck, upper trunk, and shoulders), and hyperkeratosis of the palms and soles. The skin was pale and had an orange-peel appearance, tight and firm, but she had erythema and hyperpigmentation of the upper trunk. She had joint symptoms in distal interphalangeal (DIP), metacarpophalangeal (MCP), and humeral joints, fatigue, dyspnoea, and gastrointestinal dysfunction. She had difficulty in opening her eyes, and had thick, tight skin on her fingers. In the laboratory tests haemoglobin (Hb), leucocytes, and thrombocytes were normal. Erythrocyte sedimentation rate (ESR) was 36 mm/h, eos 0.7 (normal range 0.1–0.4), and C-reactive protein (CRP) 7 mg/L, antinuclear antibodies (ANA) were 160 (normal < 160), extractable nuclear antigen (ENA) 0.7 (normal < 0.7), rheumatoid factor (RF) 12 IU (normal < 14). Spirometry was abnormal: forced vital capacity (FVC) 2, 17 (72%), forced expiratory volume in 1 s (FEV1): 1.79 (74%), FEV%: 83 (102%). Diffusion tests showed restrictive lung disease, Diffusing Capacity of the Lung for Carbon Monoxide (DLCO): 4.8 mmol/kPa min (72%), DLCO for alveolar volume (DLCO/VA): 1.28 mmol/kPa min/L (81%). High-resolution computed tomography (HRCT) was normal. In the skin histopathology there were swollen and oedematous collagen fibres in the dermis and subcutaneous tissues, there was no proliferation of fibroblasts, and the elastic fibres were normal. The patient was diagnosed with scleredema.

Differential diagnosis: Scleroderma, eosinophilic fasciitis, other connective tissue diseases, scleromyxoedema.

Treatment: No established treatment is known. Patients with DM and scleredema have symptoms for years. Tight glycaemic control is recommended. The disease is progressive and unremitting. Our patient was treated with azathioprine and ultraviolet (UV)A1 phototherapy.

ADIPONECTIN AS A CATABOLIC FACTOR IN OSTEOARTHRITIS (OA). CORRELATION TO OA BIOMARKERS COMP AND MMP-3, AND EFFECTS ON NO, MMP-3, AND IL-6 PRODUCTION IN HUMAN OA CARTILAGE

S Juslin1, K Vuolteenaho1, R Nieminen1, T Moilanen1,2, E Moilanen1

1The Immunopharmacology Research Group, Medical School, University of Tampere, Tampere University Hospital, Tampere, and 2Coxa Hospital for Joint Replacement, Tampere, Finland

Objectives: Adiponectin is an adipokine regulating insulin resistance and immune response. The role of adiponectin in osteoarthritis (OA) and cartilage metabolism is unclear although significant concentrations of adiponectin have been measured in OA synovial fluid. In the present study, we examined the relationship between adiponectin and biomarkers of cartilage degradation in OA [i.e. cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase (MMP)-3], in male OA patients, and also the effects of adiponectin on human OA cartilage.

Methods: Blood samples were obtained from 35 male OA patients [body mass index (BMI) 29.3 ± 0.8 kg/m2, age 69.5 ± 1.6 years; mean ± SEM]. Tissue cultures were carried out with cartilage samples collected from OA patients undergoing total knee replacement surgery.

Results: Plasma adiponectin (2.5 ± 1.3 μg/mL; mean ± SEM) correlated with serum COMP (r = 0.55, p = 0.001) and plasma MMP-3 (r = 0.34, p = 0.046). In tissue culture experiments, adiponectin induced the expression of inducible nitric oxide synthase (iNOS), and production of NO, interleukin (IL)-6, and stromelysin-1 (MMP-3) in human OA cartilage. The effects of adiponectin on NO and IL-6 production were mediated through mitogen-activated protein (MAP) kinases Erk1/2, p38, and JNK, while the p38 pathway was involved in the adiponectin-induced effect on MMP-3 production.

Conclusions: Adiponectin levels were found to correlate to biomarkers of OA progression, COMP and MMP-3, in male OA patients. Adiponectin was also shown to enhance the production of modulators of cartilage metabolism, NO, IL-6, and MMP-3 in human OA cartilage cultures in vitro. The findings support the idea of adiponectin as a catabolic factor in OA.

DESTRUCTIVE ROLE OF LEPTIN IN OSTEOARTHRITIS (OA). CORRELATION WITH MMP-1 AND MMP-3 IN SYNOVIAL FLUID FROM OA PATIENTS AND EFFECTS IN HUMAN OA CARTILAGE

A. Koskinen1, K. Vuolteenaho1, R. Nieminen1, T. Moilanen1,2, E. Moilanen1

1The Immunopharmacology Research Group, Medical School, University of Tampere and Tampere University Hospital, Tampere, and 2Coxa Hospital for Joint Replacement, Tampere, Finland

Objectives: Obesity in an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences the susceptibility to or pathogenesis of OA. Leptin is an adipokine regulating energy balance and appetite, and it has also recently been related to arthritis as a proinflammatory factor. In OA, proteolytic degradation of cartilage is mediated by matrix metalloproteinases (MMPs). In the present study, the levels of leptin and MMPs were measured in synovial fluid from OA patients and the effects of leptin on MMP-1, MMP-3, MMP-8, and MMP-13 production in human OA cartilage were studied.

Methods: Synovial fluid samples were obtained from 84 OA patients [54 female and 30 male patients, body mass index (BMI) 30.9 ± 0.6 kg/m2, age 70.4 ± 9.4 years; mean ± SEM]. Cartilage tissue obtained from the leftover pieces of total knee replacement surgery from patients with OA was investigated in tissue culture. MMP production in the culture medium was measured by immunoassay (multiplex bead array method, Luminex).

Results: Synovial fluid leptin (20.4 ± 2.2 ng/mL; mean ± SEM) correlated with synovial fluid MMP-1 (r = 0.41, p < 0.001, 16.7 ± 1.5 ng/mL) and MMP-3 (r = 0.51, p < 0.001, 823.2 ± 73.3 ng/mL). In cartilage culture, leptin alone and in combination with interleukin (IL)-1 enhanced the production of collagenases MMP-1 and MMP-13, and stromelysin-1 (MMP-3) in human OA cartilage, while collagenase-2 (MMP-8) concentrations remained undetectable. Leptin-induced MMP production was dependent on activation of PKC, JNK, and NF-κB pathways.

Conclusions: Leptin levels correlated with the concentrations of the destructive enzymes MMP-1 and MMP-3 in synovial fluid from OA patients. Of note, leptin also enhanced the production of the destructive enzymes MMP-1, MMP-3, and MMP-13 in human OA cartilage in vitro. The findings support the idea of adipocytokine leptin as a catabolic factor in the pathogenesis of OA, and as a possible link between obesity and OA.

MAP KINASE PHOSPHATASE-1 LIMITS THE EXPRESSION OF PROINFLAMMATORY GENES TNF, IL-6, IL-8, AND COX-2

T Turpeinen, R Nieminen, E Moilanen, R Korhonen

The Immunopharmacology Research Group, University of Tampere, Finland, and Tampere University Hospital, Tampere, Finland

MAP kinases (ERK ½, p38, and JNK) regulate immune responses and the expression of inflammatory genes, such as cytokines, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS). MAP kinase phosphatase-1 (MKP-1) dephosphorylates and thereby negatively regulates the activity of MAP kinases p38 and JNK. In the present study, the role of MKP-1 in the regulation of the expression of inflammatory genes was investigated in human A549 cells and in mouse primary macrophages and J774 macrophage cell lines.

Human A549 epithelial cells and J774 mouse macrophages were stimulated with cytokines [tumour necrosis factor (TNF), interleukin (IL)-1β, interferon (IFN)-γ, 10 ng/mL each) or lipopolysaccharide (LPS) to activate p38 and JNK and induce cytokine and COX-2 expression. Cytokines induced the phosphorylation of p38 and JNK at 30 min, which was reverted to basal level at 1 h. Stimulation of A549 cells induced IL-6, IL-8, and COX-2 mRNA and protein expression and the stimulation of J774 macrophages with LPS induced TNF, IL-6, and COX-2 expression. IL-6, IL-8, and COX-2 mRNA and protein expression was inhibited by p38 inhibitors SB202190 and BIRB 796 but not with a JNK inhibitor VIII. Stimulation with cytokines (A549 cells) or LPS (J774 cells) induced the expression of MKP-1 during 1 h incubation. Down-regulation of MKP-1 with siRNA decreased expression of MKP-1 and increased p38 and JNK phosphorylation. MKP-1 siRNA also increased IL-6, IL-8, and COX-2 mRNA and protein expression in A549 cells, and TNF, IL-6, and COX-2 expression in J774 cells. The effect of MKP-1 on LPS-induced expression of TNF, IL-6, and COX-2 was tested in mouse primary bone-marrow macrophages isolated from wild-type and MKP-1 knock-out mice, also. The expression of TNF, IL-6, and COX-2 was increased in macrophages from MKP-1 knock-out mice as compared to those from wild-type mice.

In conclusion, our result suggests that MKP-1 regulates the phosphorylation of p38 and JNK MAP kinases in macrophages and in epithelial cells. MKP-1 negative regulates the expression of TNF, IL-6, IL-8, and COX-2 by limiting and coordinating p38 activity induced by inflammatory signals.

MAP KINASE PHOSPHATASE-1 NEGATIVELY REGULATES THE EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE

R Korhonen, T Turpeinen, R Nieminen, T Harmanen, O Sareila, E Moilanen

The Immunopharmacology Research Group, University of Tampere, Finland, and Tampere University Hospital, Tampere, Finland

The p38 MAP kinase pathway is a major signalling pathway involved in the regulation of innate and adaptive immune responses. MAP kinase phosphatase-1 (MKP-1) is a protein phosphatase that has been shown to negatively regulate the phosphorylation (i.e. activity) of MAP kinases and immune responses in mice. In the present study, the effect of MKP-1 on the phosphorylation of p38 MAP kinase and the expression of iNOS was investigated in human and murine cells.

Human A549 epithelial cells and mouse J774 macrophages were stimulated with cytokines (TNF, IFN-γ IL-1β; 10 ng/mL each) or with LPS (10 ng/mL), respectively. p38 phosphorylation was increased in 30 min after adding the stimulus and it was reverted to basal level at 1 h. Cytokines (A549 cells) and LPS (J774 cells) induced iNOS mRNA and protein expression and NO production and those were inhibited by p38 MAP kinase inhibitors SB202190 and BIRB 796. MKP-1 expression was increased at 1 h in cytokine-stimulated A549 cells and in LPS-stimulated J774 macrophages as well as mouse primary bone-marrow macrophages. Down-regulation of MKP-1 with MKP-1-specific siRNA markedly increased cytokine-induced p38 phosphorylation and enhanced iNOS mRNA and protein expression and NO production in human A549 cells and mouse J774 macrophages. Of note, LPS-induced iNOS expression was markedly increased also in bone-marrow macrophages from MKP-1 knock-out mice as compared to macrophages from wild-type mice.

In conclusion, MKP-1 is an important negative regulatory factor for iNOS expression in both human and murine cells by suppressing p38 MAP kinase phosphorylation.

HOMOCITRULLINE ANTIBODIES CROSS-REACT WITH CITRULLINE

M-K Koivula1, S Turunen1, L Risteli1, A Karjalainen2, M1 Hakala3, J Risteli1

Institutes of 1Diagnostics and 2Clinical Medicine, University of Oulu, Oulu and 3Rheumatism Foundation Hospital, Heinola and Department of Musculoskeletal Medicine and Rehabilitation, University of Tampere, Tampere, Finland

Objectives: To clarify the possible roles of protein-bound homocitrulline in causing an antibody response to citrulline and as a confounding factor in citrulline detection assays.

Methods: Native, carbamylated, and citrullinated albumin were used for testing the specificity of commercial antibodies against modified citrulline by western blot. Rabbits were immunized with human albumin and/or bone type I collagen, both treated with cyanate to produce homocitrulline. These antisera were tested for binding to cyclic citrullinated peptide (CCP2), mutated citrullinated vimentin (MCV), and type I or II collagen telopeptides containing either citrulline or homocitrulline. Sera of 12 patients with rheumatoid arthritis (RA) were tested for binding to citrullinated and homocitrullinated type I collagen telopeptides.

Results: The allegedly specific commercial antibodies against chemically modified citrulline were found to recognize both homocitrulline- and citrulline-containing albumins. The rabbits immunized with proteins containing homocitrulline produced high-affinity antibodies against CCP2 and to a lesser extent against MCV. The antisera also bound homocitrulline-containing collagen telopeptides and, less strongly, citrulline-containing telopeptides. When arginine was replaced with homocitrulline in the telopeptide sequences, their binding to the RA sera could be inhibited by both soluble citrullinated and homocitrulline-containing peptides.

Conclusions: Homocitrulline, which is a structural analogue of citrulline, longer by one carbon and readily formed in the body, can be involved in raising citrulline-recognizing antibodies in experimental animals and can also cause false-positive reactions in assays for citrulline. Homocitrulline-recognizing antibodies are also present in the sera of RA patients.

INHIBITION OF PROTEIN KINASE Cδ DOWN-REGULATES THE EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE IN ACTIVATED MACROPHAGES

T Leppänen1, R Korhonen1, RK Tuominen2, E Moilanen1

1The Immunopharmacology Research Group, Medical School, University of Tampere and Tampere University Hospital, Tampere, and 2The Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

Background and aim: Proinflammatory cytokines and bacterial products trigger inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in inflammatory cells. Increased production of NO has been shown to enhance inflammation and mediate tissue damage in rheumatoid arthritis (RA) and other inflammatory diseases. Protein kinase C (PKC) is a family of 12 serine-threonine protein kinase isoenzymes involved in signal transduction pathways related to inflammatory responses. In the present study we investigated the role of PKCδ isoenzyme in the regulation of iNOS expression and NO production in activated macrophages.

Methods: The effects of PKCδ on lipopolysaccharide (LPS)-induced iNOS expression and NO production were studied by using the PKCδ inhibitor rottlerin and by downregulating PKCδ expression with the siRNA method. The effects on iNOS protein and mRNA expression were determined by western blotting and by quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. NO production was measured by the Griess method. In addition, the effects of PKCδ inhibition, by either rottlerin or siRNA, on the activity of transcription factors and iNOS mRNA and protein degradation were determined.

Results: iNOS expression and NO production were down-regulated by rottlerin and by PKCδ-specific siRNA. However, inhibition of PKCδ, by either rottlerin or siRNA, did not affect iNOS mRNA expression or mRNA decay. Rottlerin did not significantly affect the activity of transcription factors NF-κB or STAT1. Instead, rottlerin seemed to enhance iNOS protein degradation in a proteasome-independent manner.

Conclusions: The results show that PKCδ up-regulates the expression of iNOS in activated macrophages and serves therefore as a potential therapeutic target in diseases such as RA, which are complicated by excessive NO production via the iNOS pathway.

IMMIGRATION CHECK FOR NEUTROPHILS IN RA LINING: LAMININ α5 LOW EXPRESSION REGIONS ACT AS EXIT POINTS

P Poduval1,2, I Virtanen2, Y T. Konttinen1,3,4

1Department of Medicine/Invärtes Medicin, Helsinki University Central Hospital, 2Department of Anatomy, University of Helsinki, 3ORTON Orthopaedic Hospital of the Invalid Foundation Helsinki, and 4COXA Hospital for Joint Replacement, Tampere, Finland

Objective: A correlation exists between the absence of α5 laminin and transit checkpoint fenestrations in vascular basement membranes. We hypothesized that similar laminin α5 low expression regions might exist in synovial lining, which, although lacking basement membrane, contains all basement membrane components in its interstitial matrix.

Methods: Laminin α4 and α5 chains and lactoferrin were stained using immunofluorescence and cathepsin G and neutrophil elastase using immunoperoxidase. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to measure laminin α4 and α5 mRNA copy numbers in cultured synovial fibroblasts, without/with tumour necrosis factor (TNF)-α and interleukin (IL)-1β.

Results: α4 and α5 laminin chains were found in the intercellular matrix in the synovial lining of trauma and revision total hip replacement. Laminin α5 was weaker in osteoarthritis (OA) and rheumatoid arthritis (RA), and RA synovial lining also contained local low expression areas. Double staining disclosed convergence of lactoferrin-degranulating neutrophils towards these laminin α5 low expression regions. In cultured OA synovial fibroblasts, laminin α5 mRNA decreased (p < 0.05) at 1 ng/mL TNF-α and was not found at all in cultured resting or cytokine-stimulated RA fibroblasts. Degranulation of cathepsin G and neutrophil elastase was seen in neutrophils passing through blood vessels or synovial lining.

Conclusion. In RA, migrating neutrophils seem to use laminin α5 chain low expression regions to exit synovial tissue to enter synovial fluid. Transmigrating neutrophils remodel intercellular matrix by releasing their proteolytic granular contents to enhance these low expression checkpoints and/or to produce chemotactic stimuli. In RA fibroblasts this is facilitated by cytokine-mediated down-regulation or lack of laminin α5 synthesis.

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