New vessels, new approaches: angiogenesis as a therapeutic target in musculoskeletal disorders.
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Musculoskeletal disorders such as rheumatoid arthritis (RA) and osteoarthritis are a common cause of pain and disability. The vasculature is an important component of the musculoskeletal system, and vascularization is a key event in the development of normal cartilage and bone. By promoting the delivery of nutrients, oxygen and cells, blood vessels help maintain the structural and functional integrity of joints and soft tissue and may facilitate tissue repair and healing. The identification of pro-angiogenic mediators such as vascular endothelial growth factor (VEGF) has led to the development of antiangiogenic therapies for the treatment of neoplastic diseases. The important role of angiogenesis, and especially VEGF, in the pathogenesis of joint disorders such as RA suggests that antiangiogenic therapy may be a useful adjunct to existing approaches in RA. (+info)
The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis.
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OBJECTIVE: Spontaneous arthritis in the KRN transgenic mouse model is due to the autoreactivity of the transgenic T cell receptor (TCR) against Ag7 major histocompatibility complex (MHC) molecules, which leads to strong but incomplete clonal deletion. We sought to determine whether other stimuli triggering this receptor might provoke arthritis, whether the apparently systemic reactivity might have some joint-preferential component explaining the paradoxical arthritic phenotype, and whether the transgenic receptor was the only one required or whether other TCRs might be ferried along in a leaky tolerance process. METHODS: Crosses and radiation chimeras involving a panel of transgenic and knockout mouse lines were used. The reactivity of the KRN TCR was tested in carboxyfluorescein diacetate succinimidyl ester-transfer experiments and in crosses with transgenic or inbred mice expressing other molecules that stimulate the KRN receptor (the mls-1a superantigen, the Aalpha(k69)Abeta(k) mutant MHC molecule). The arthritogenic capacity of T cells expressing only the KRN TCR was tested by crossing to recombination-activating gene-knockout mice, and constructing bone marrow chimeras with precursors to these strictly monoclonal T cells. RESULTS: The data show that the KRN TCR itself is the only receptor needed. It needs to be triggered by the Ag7 molecule loaded with self-peptides in order to provoke arthritis, but there is no indication of preferential presentation of joint-derived peptides. CONCLUSION: Arthritis can be generated by systemic recognition of self-MHC-peptide complexes by autoreactive T cells. This triggers B lymphocytes to produce arthritogenic antibodies, without the involvement of joint-specific T cell targets. (+info)
Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy.
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OBJECTIVE: In both rheumatoid arthritis and collagen-induced arthritis (CIA), the nuclear factor kappaB (NF-kappaB) transcription factor plays a pivotal role in the coordinated transactivation of many cytokines related to pathogenesis. This study investigated whether synthetic double-stranded DNA that show a high affinity for NF-kappaB could be introduced in vivo as "decoy" cis elements to bind the transcription factor and block the activation of such proinflammatory cytokine genes as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha), and thus suppress the severity of joint destruction. METHODS: NF-kappaB decoy oligonucleotides (ODN) were introduced by an intraarticular injection into the bilateral hind ankle joints of CIA rats using the hemagglutinating virus of Japan (HVJ)-liposome method. Joint destruction was evaluated by histology and radiography. IL-1 and TNFalpha levels were assessed by enzyme-linked immunosorbent assay and Northern blot analysis. RESULTS: Using the HVJ-liposome method, the presence of fluorescein isothiocyanate-labeled ODN in the synovium was confirmed until 28 days after intraarticular injection. In vivo transfection of NF-kappaB decoy ODN by an intraarticular injection into CIA rats decreased the severity of hind-paw swelling. Histologic and radiographic studies showed a marked suppression of joint destruction treated by NF-kappaB decoy ODN transfection. This treatment method also suppressed the production of IL-1 and TNFalpha in the synovium of arthritic joints. CONCLUSION: The present results demonstrate that administration of NF-kappaB decoy ODN in arthritic joints of rats with CIA led to an amelioration of arthritis. These findings suggest that intraarticular transfection of NF-kappaB decoy ODN may provide a useful therapeutic approach for the treatment of inflammatory arthritis. (+info)
Identification of Mycoplasma fermentans in synovial fluid samples from arthritis patients with inflammatory disease.
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Since 1970 Mycoplasma fermentans has been suspected of being associated with rheumatoid arthritis. However, this association has been difficult to prove, and this has been our goal. The distribution of M. fermentans was studied in the synovial fluid of patients suffering from different arthritides. Samples of synovial fluid were taken from patients with well-defined disease and a clear diagnosis. After removal of the inflammatory cells and hyaluran, they were treated with proteinase K and tested by a single or fully nested PCR with primers directed against part of the two 16S rRNA genes of M. fermentans. The product was sequenced automatically, by using an ALF Express automatic sequencer, to confirm the mycoplasma species and to identify the strain since the two genes were usually found to be polymorphic. This was also true of the type strain, strain PG18. M. fermentans was detected in 23 of 26 (88%) rheumatoid arthritis patients, and four different strains were found. It was also found in 7 of 8 (88%) of the nonrheumatoid inflammatory arthritis patient group, which consisted of one patient with reactive arthritis, one patient with pauciarticular juvenile chronic arthritis, two patients with gout, two patients with ankylosing spondylitis, and two patients with psoriatic arthritis, only one of whom was infected with M. fermentans. It was not detected in any of the 10 osteoarthritis patients. M. fermentans was therefore found to be a variable and very common organism in arthritic patients with inflammatory joint exudates and may well prove to be important in the etiology of the diseases. (+info)
Healthcare utilization associated with dyspepsia in patients with arthritis.
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OBJECTIVE: To compare gastrointestinal-related healthcare resource utilization in arthritis patients with and without dyspepsia. STUDY DESIGN: A historical cohort study based on a claims database. PATIENTS AND METHODS: Data were obtained from the MarketScan database. Adult patients with a diagnosis of arthritis (International Classification of Diseases, 9th Revision [ICD-9] codes 714.0-715.9) during 1992 and 1993 were included; individuals with a diagnosis of dyspepsia within the first 3 months of their arthritis diagnosis were considered study case patients. Each case patient was matched with 4 nondyspeptic arthritis patients based on age, gender, employment status, and type of insurance plan. Healthcare resource utilization in terms of outpatient services and inpatient admissions during the first year after the initial arthritis diagnosis was compared between the case and control groups. RESULTS: A total of 503 case and 2146 control patients were identified. There were no significant differences in demographic characteristics between the 2 groups. Dyspeptic patients (cases) had a significantly higher rate of claims for endoscopic procedures (odds ratio [OR] = 10.0, P < .01) than nondyspeptic patients (controls). Patients with dyspepsia also had a significantly higher claim rate of gastrointestinal ulcer or bleeding (OR = 4.2, P < .01) and were more likely to be hospitalized at least once (OR = 1.4, P < .01). Dyspeptic patients had overall higher frequencies of use of outpatient services (53.9 vs 32.5 claims per patient, P < .001) and higher costs for both inpatient admission and outpatient services than nondyspeptic patients. CONCLUSION: Dyspeptic arthritis patients have higher healthcare resource utilization and associated costs than nondyspeptic arthritis patients. (+info)
Occupational use of precision grip and forceful gripping, and arthrosis of finger joints: a literature review.
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A systematic review of arthrosis of finger joints in relation to occupational exposure revealed 11 epidemiological studies and 13 case reports. All studies but one were cross-sectional rendering demonstration of causation problematic. The reviewed literature also had drawbacks relating to exposure classification, confounding and non-attendance. Four studies showed an association between extensive use of precision grip and development of arthrosis of the distal interphalangeal joints of fingers. Two studies found an association between forceful gripping and the occurrence of arthrosis involving the metacarpophalangeal joints. Arthrosis of the proximal interphalangeal joints and first carpo-metacarpal joints was not related to any specific occupational task. Well-designed studies are needed to further elucidate this possible occupational hazard. (+info)
Thermal and mechanical antinociceptive action of spinal vs peripherally administered clonidine in the rat inflamed knee joint model.
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It has been demonstrated recently that in addition to its spinal analgesic actions, the alpha 2 adrenoreceptor agonist clonidine also has peripheral analgesic activity. Few data are available regarding the antinociceptive effects of spinal vs peripherally delivered clonidine in inflammatory pain. Thus we have studied spinal (intrathecal = i.t.) and peripheral (intra-articular = i.a.) administration of clonidine in the rat inflamed knee joint model. Thermal and mechanical antinociception was assessed in rats over 28 h using a modified Hargreaves box and von Frey hairs after induction of tonic persistent inflammatory pain by injection of a kaolin-carrageenan mixture into the right knee joint. Thirty minutes after injection of kaolin-carrageenan, clonidine was administered via an i.t. catheter or by i.a. injection into the right inflamed knee joint or by subcutaneous injection (s.c.) (highest effective intra-articular dose). The specific site of action was assessed using the alpha 2 antagonist yohimbine i.t., i.a. or s.c. Clonidine i.t. resulted in thermal and mechanical antinociception during ongoing inflammation, which was not enhanced by inflammation. In contrast, i.a. delivery of clonidine, which also produced a dose-dependent thermal and mechanical antinociceptive effect, revealed a leftward shift in the antinociceptive activity produced by ongoing inflammation. Yohimbine inhibited the antinociceptive action of clonidine at the site of delivery. We suggest that clonidine produces potent thermal and mechanical antinociception regardless of the route of administration. However, chronic inflammatory processing appears to enhance the antinociceptive efficacy of the peripheral alpha 2 agonist. (+info)
Genotype-phenotype correlation in a large group of Turkish patients with familial mediterranean fever: evidence for mutation-independent amyloidosis.
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OBJECTIVES: Differences in clinical manifestations of familial Mediterranean fever (FMF) between different ethnic groups have been documented. The FMF gene was recently cloned and four missense mutations (Met694Val, Met680Ile, Val726Ala, and Met694Ile) that account for a large percentage of the patients were identified. The results of initial mutation studies have led to the hypothesis that phenotypic variation of the disease may be attributable to the existence of some of these mutations. The purpose of this study was to evaluate whether this phenotypic variation is associated with the existence of particular mutations in Turkish FMF patients living in Turkey. METHODS: Four missense mutations and genotype-phenotype correlation were investigated in 167 Turkish FMF patients. The patients were grouped according to the presence of the Met694Val and the Met680Ile mutations, and 12 clinical parameters were compared between the groups. RESULTS: The presence of the Met694Val mutation was not found to be associated with a severe form of the disease or the development of amyloidosis. Arthritis frequency was found to be lower in the patients with homozygous Met680Ile mutation. CONCLUSIONS: None of the four missense mutations is associated with a severe disease or the development of amyloidosis in Turkish FMF patients living in Turkey. The influence of unknown environmental factors and/or the presence of other genetic changes are necessary to explain the phenotypic variation of the disease and the development of amyloidosis. (+info)