Shu Kobayashi

A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis

OBJECTIVE Environmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis. METHODS Human synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with alpha-naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDD-AhR interaction, we used inhibitors of nuclear factor-kappaB (NF-kappaB) and extra-cellular stimulus-activated kinase (ERK). RESULTS Higher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1beta, IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-kappaB and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-alpha. CONCLUSION TNF-alpha activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-kappaB and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.

Molecular aspects of rheumatoid arthritis: role of environmental factors

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that affects 0.5–1% of the population. RA causes progressive joint destruction that leads to the restriction of activities of daily living and deterioration of quality of life. Although the pathogenesis of RA has not yet been fully elucidated, it is considered to be a complex, multifarious disease that is influenced by both genetic and environmental factors. Genetic influences that contribute to RA susceptibility have been demonstrated both in studies of twins and families, as well as in genome‐wide linkage scans, and it is estimated that genetic factors are responsible for 50–60% of the risk of developing RA. Thus, environmental factors may explain the remaining risk of developing RA. A large variety of environmental factors such as infectious agents, smoking, sex hormones, pregnancy etc. have been extensively studied previously. Understanding of how these factors contribute to the development of RA may lead to the better understanding of pathogenesis of RA.

A role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis

We studied the role of monocyte chemoattractant (MCP)‐4/CCL13 in the pathogenesis of rheumatoid arthritis (RA). MCP‐4 was highly expressed in cartilage from RA patients. Interferon‐γ significantly stimulated MCP‐4/CCL13 production in human chondrocytes, and this effect was enhanced in combination with interleukin‐1β or tumor necrosis factor‐α. MCP‐4/CCL13 induces the phosphorylation of extracellular signal‐regulated kinase in fibroblast‐like synoviocytes and activates cell proliferation, and PD98059 completely inhibits these effects. These data suggest that interferon‐γ in combination with interleukin‐1β/tumor necrosis factor‐α activates the production of MCP‐4/CCL13 from chondrocytes in RA joints, and that secreted MCP‐4/CCL13 enhances fibroblast‐like synoviocyte proliferation by activating the extracellular signal‐regulated kinase mitogen‐activated protein kinase cascade.

ITGAV polymorphism and disease susceptibility in a Japanese rheumatoid arthritis population.

A research article by Jacq and colleagues reported an association between rheumatoid arthritis (RA) and the rs3738919-C allele in the ITGAV gene which encodes alphav subunit of the integrin alpha v beta3 in the European Caucasian population.

Stat3 as a potential therapeutic target for rheumatoid arthritis

Rheumatoid arthritis (RA) is a multi-factorial disease characterized by chronic inflammation and destruction of multiple joints. To date, various biologic treatments for RA such as anti-tumor necrosis factor alpha antibodies have been developed; however, mechanisms underlying RA development remain unclear and targeted therapy for this condition has not been established. Here, we provide evidence that signal transducer and activator of transcription 3 (Stat3) promotes inflammation and joint erosion in a mouse model of arthritis. Stat3 global KO mice show early embryonic lethality; thus, we generated viable Stat3 conditional knockout adult mice and found that they were significantly resistant to collagen-induced arthritis (CIA), the most common RA model, compared with controls. We then used an in vitro culture system to screen ninety-six existing drugs to select Stat3 inhibitors and selected five candidate inhibitors. Among them, three significantly inhibited development of arthritis and joint erosion in CIA wild-type mice. These findings suggest that Stat3 inhibitors may serve as promising drugs for RA therapy.

A case of isolated gouty tophus in a patient without a previous history of gouty arthritis.

intensity of the mass (arrows) was nearly as isointense as that of muscle on T1-weighted images (Upper row Fig. 1) and heterogeneous low to heterogeneous high (arrows) on T2-weighted images (Lower row Fig. 1). MR imaging also revealed osteolysis of the metatarsal head induced by the mass. Microscopic examination of the contents of the mass obtained by puncture revealed monosodium urate crystals (Fig. 2). Gouty tophi without history of gouty arthritis have rarely been reported. A literature search (Table 1, Supplemental Digital Content 1, http://links.lww.com/RHU/A6) suggested that female gender, reduced renal function, and use of hyperuricemia-inducing drugs are risk factors for the development of gouty tophus without gouty arthritis. However, the present case is unique in that he had none of these risk factors. This case indicates that gouty tophi should be considered during the differential diagnosis of soft tissue masses, even in hyperuricemic patients without previous gouty arthritis. From the Institute of Rheumatology, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan. Correspondence: Shu Kobayashi, Institute of Rheumatology, Tokyo Women’s Medical University, 10 –22 Kawada, Shinjuku, Tokyo 162–0054, Japan. E-mail: shu-@zd6.so-net.ne.jp. Copyright

Detection of calcium pyrophosphate dihydrate crystals in knee meniscus by dual-energy computed tomography

BackgroundCalcium pyrophosphate dihydrate (CPPD) crystals are commonly observed in osteoarthritic joints. The aim of our study was to investigate the efficacy of a dual-energy computed tomography (DECT) for detecting CPPD crystals in knee meniscus.MethodsTwenty-six patients undergoing primary total knee arthroplasty were included in the study. Radiographs of knee joint and synovial fluid specimens were analyzed for the presence of CPPD crystals. Meniscus extracted during surgery was scanned using DECT. Sensitivity and specificity of DECT and radiograph for detecting CPPD crystals were calculated against a reference standard (polarizing light microscopy of synovial fluid aspirate). Meniscus in which CPPD crystals were suspected with DECT was further examined to confirm the crystals using a polarized microscopy.ResultsCPPD crystals in synovial fluid were observed in 9 (36%) patients. The sensitivity and specificity of DECT in the detection of CPPD crystals, against microscopic identification, were 77.8 and 93.8%, respectively. The sensitivity and specificity of conventional radiography in the detection of CPPD crystals were 44.4 and 100%, respectively. DECT was able to detect the area where CPPD crystals were deposited in the meniscus.ConclusionDECT provides good diagnostic sensitivity and specificity for detection of CPPD crystals in knee meniscus as well as spatial information about CPPD crystals. DECT is currently a research tool, but we believe that DECT can be a useful instrument to diagnose CPPD deposition disease, especially for the regions where aspiration is difficult to be performed such as pubic symphysis, atlantoaxial joint, interphalangeal joint.

Factors affecting one-leg standing time in patients with end-stage knee osteoarthritis and the age-related recovery process following total knee arthroplasty.

BackgroundThe aims of the present study were to investigate the factors affecting one-leg standing (OLS) time in patients with end-stage knee osteoarthritis (OA) and to clarify the age-related recovery process following total knee arthroplasty (TKA) in the early postoperative period.MethodsA total of 80 knees of 40 patients with knee OA were enrolled. They were asked to perform relaxed standing on one leg for as long as possible. First, OLS time was measured. Second, age, body mass index, knee flexion angle during (KFA) OLS, femorotibial angle (FTA) during OLS, and a visual analogue scale (VAS) for pain were evaluated. Multiple regression analysis was done to identify the factors affecting OLS time. In addition, the recovery process was compared between older and younger patients after TKA.ResultsA larger KFA during OLS, older age, and larger FTA were significantly associated with shorter OLS time. After TKA, postoperative OLS time in older patients did not improve significantly by postoperative day 20, while the time in younger patients improved significantly from postoperative day 19.ConclusionsEven if subjective knee pain and KFA during OLS improved, longer rehabilitation was required to improve OLS time in older patients in the early postoperative period.

Local infiltration of analgesia and sciatic nerve block provide similar pain relief after total knee arthroplasty

BackgroundAlthough femoral nerve block provides satisfactory analgesia after total knee arthroplasty (TKA), residual posterior knee pain may decrease patient satisfaction. We conducted a randomized controlled trial to clarify the efficacy of the sciatic nerve block (SNB) and local infiltration of analgesia with steroid (LIA) regarding postoperative analgesia after TKA, when administrated in addition to femoral nerve block (FNB).MethodsSeventy-eight patients were randomly allocated to the two groups: concomitant administration of FNB and SNB or FNB and LIA. The outcome measures included post-operative pain, passive knee motion, C-reactive protein level, time to achieve rehabilitation goals, the Knee Society Score at the time of discharge, patient satisfaction level with anesthesia, length of hospital stay, surgical time, and complications related to local anesthesia.ResultsThe patients in group SNB showed less pain than group LIA only on postoperative hours 0 and 3. Satisfactory postoperative analgesia after TKA was also achieved with LIA combined with FNB, while averting the risks associated with SNB. The influence on progress of rehabilitation and length of hospital stay was similar for both anesthesia techniques.ConclusionsThe LIA offers a potentially safer alternative to SNB as an adjunct to FNB, particularly for patients who have risk factors for sciatic nerve injury.

IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.