Associations of disease duration and anti-citrullinated peptide antibody status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis: Post hoc analysis of a multicentre, real-world observational study in Japan (ORIGAMI).

OBJECTIVES: The aim of the article is to investigate the associations of disease duration and anti-cyclic citrullinated peptide antibody (ACPA) status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis (RA). METHODS: We performed post hoc analyses of the Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study of biologic-naïve RA patients aged ≥20 years with moderate disease activity who were prescribed abatacept. Changes in the Simplified Disease Activity Index (SDAI) and Japanese Health Assessment Questionnaire (J-HAQ) at 4, 24, and 52 weeks of treatment were analysed in patients divided according to ACPA serostatus (positive/negative), disease duration (<1/≥1 year), or both. RESULTS: SDAI scores decreased from baseline in all groups. SDAI scores tended to decrease more in the ACPA-positive group and disease duration <1-year group than in the ACPA-negative group and disease duration ≥1-year group, respectively. In the disease duration <1-year group, SDAI tended to decrease more in the ACPA-positive group than in the ACPA-negative group. Disease duration was independently associated with the change in SDAI and SDAI remission at Week 52 in multivariable regression models. CONCLUSIONS: These results suggest that starting abatacept within 1 year of diagnosis was associated with greater effectiveness of abatacept in biologic-naïve patients with RA and moderate disease activity.

Cytokine Profile From the Ligamentum Flavum in Patients with Ossification of the Posterior Longitudinal Ligament in the Cervical Spine.

STUDY DESIGN: Histological, immunohistochemical, and suspension array analyses of cytokine expression in human cervical ossification of the posterior longitudinal ligament (OPLL). OBJECTIVES: The aim of this study was to determine whether changes in the cytokine profile reflect the maturation of chondrocytes and osteoblasts are associated with OPLL development. SUMMARY OF BACKGROUND DATA: OPLL progresses gradually over a prolonged period and may lead to serious spinal cord complications. However, treatment methods only include conservative therapy for neurological symptoms or surgical decompression, whereas preventive therapy for OPLL remains nonexistent. METHODS: Ligamentous samples were harvested from 24 patients with OPLL who underwent spinal surgery, and five control samples from cervical spondylotic myelo/radiculopathy patients without OPLL. Tissue sections were used for immunohistochemical studies and primary cells were cultured from the ligamentous samples for cytokine profiling. Using a suspension array system, concentrations of 27 inflammatory cytokines or growth factors were measured to generate the cytokine profiles. RESULTS: Suspension array and immunoblot analysis revealed significant increments in the levels of interleukin (IL)-6, IL-1α, basic fibroblast growth factor, and RANTES in patients with OPLL. Immunohistochemical analysis further revealed that these factors were present in mesenchymal cells within the degenerative portion of the ligamentous matrix. CONCLUSION: Our findings suggest that specific changes in the cytokine profile during ossification promote osteoblast differentiation, thereby providing new insights into OPLL pathogenesis. Moreover, this work supports the development of a new therapeutic method for preventing OPLL progression by regulating the cytokine profiles.Level of Evidence: 3.

Surgical treatment of wrist joint dysfunction in rheumatoid arthritis: A report of two cases.

In rheumatoid arthritis (RA), it is important to actively treat wrist dysfunction to improve patient outcomes. Herein, we report two cases of wrist dysfunction in RA patients who required partial wrist fusion soon after drug initiation. Case 1: A 38-year-old woman was referred to our hospital because of left wrist joint pain. At the time of examination, swelling and tenderness of the left wrist joint were observed. After 6 months of medication, no improvement in symptoms was noted; therefore, partial wrist fusion was performed. Case 2: A 38-year-old woman was referred to our hospital because of right wrist joint pain. A plain X-ray image showed fusion of the carpal bones. Due to previous failure of drug treatment, the patient opted for arthrodesis. The postoperative course was good in both cases, and the pain improved. In these cases of monoarthritic RA, synovitis and bone destruction were observed, but blood tests showed no features of active disease, and drug treatment was ineffective. In such cases, early surgical treatment should be considered, rather than continuing conservative treatment, to ensure the best outcomes.

Consideration of differences in drug usage between young-onset and elderly-onset rheumatoid arthritis with target of low disease activity.

OBJECTIVES: Elderly-onset rheumatoid arthritis (EORA) is reported to differ from young-onset rheumatoid arthritis (YORA) with regard to patient background and drug treatment. We examined the amount of drug administered to patients who achieved low disease activity (LDA) for rheumatoid arthritis at our hospital. METHODS: Demographics, clinical history, and treatments were compared between patients with EORA (n = 70) and YORA (n = 190). RESULTS: There was a significant difference in the average age (73.8 vs. 57.8 years), disease duration (6.66 vs. 14.7 years), and sex (62.9% males vs. 83.7% females), but no difference in rheumatoid factor positivity (85.3% vs. 80.7%), anti-citrullinated peptide antibody positivity (86.5% vs. 87.7%), simplified disease activity index (4.28 vs. 4.59), or disease activity score 28-CRP (1.99 vs. 2.04) in the EORA and YORA groups, respectively. There were also no significant differences in prednisolone use (37.1% vs. 36.3%), amount of methotrexate administered (MTX) (1.45 vs. 1.41 mg), and MTX use (55.7% vs. 65.3%). However, the MTX dose (2.89 vs. 4.09 mg/week, p = .011) and overall biologics use (32.9% vs. 56.3%, p = .0012) were significantly lower in patients with EORA than in those with YORA. CONCLUSION: Patients with EORA may be able to achieve LDA with lower drug dosage than those with YORA.

Effects of malalignment and disease activity on osteophyte formation in knees of rheumatoid arthritis patients.

PURPOSE: Rheumatoid arthritis (RA) patients with secondary osteoarthritis (OA) in a knee joint following a total knee arthroplasty (TKA) procedure have been increasing. Here, we investigated osteophyte formation in knee joints of RA patients and associated factors. METHODS: We retrospectively examined findings of 35 knees in 30 RA patients (26 females, 4 males; mean age: 63.0 years; median disease duration: 15 years) who underwent TKA, including preoperative anteroposterior view radiographs of the knee joint. Using the ImageJ software package, osteophyte size in the medial femur (MF), medial tibia (MT), lateral femur (LF), and lateral tibia (LT) regions was also determined. RESULTS: The mean femorotibial angle was 179°, while Larsen grade was 2 in 1, 3 in 12, 4 in 18, and 5 in 2 patients. Osteophyte sizes in the MF, MT, LF, and LT regions were 37.2, 17.0, 27.2, and 4.57 mm2, respectively, and significantly greater in the medial compartment (MC; MF+MT) than the lateral compartment (LC; LF+LT) (p < 0.001). In varus cases, osteophyte size in the MC was significantly larger than normal and valgus cases (p = 0.0016). Furthermore, osteophyte size in the MC was negatively correlated with the inflammatory markers C-reactive protein (r = -0.492, p = 0.0027) and erythrocyte sedimentation rate (r = -0.529, p = 0.0016), whereas that in the LC was negatively correlated with disease activity (r = -0.589, p = 0.0023). CONCLUSION: Our results suggest that alignment and disease activity influence osteophyte formation in RA patients, with secondary OA a more prominent symptom in RA patients with controlled inflammation.

ß-Angles of hips with femoroacetabular impingement versus asymptomatic normal hips in a Japanese population: A CT-based observational clinical study.

BACKGROUND: The beta angle (ß-angle)-although used to assess femoroacetabular impingement (FAI)-has not been well evaluated. This study aimed to measure the ß-angle on multiradial computed tomography (CT) slice images of both hips with symptomatic FAI and asymptomatic normal hips to determine its optimal cutoff value for detecting FAI in a Japanese population. METHODS: CT was performed with each subject supine. The ß-angle was measured on seven radial slices (designated R0, R15, R30, R45, R60, R75, R90) that were generated at 15° intervals from the oblique axial slice through the center of the femoral neck. An a priori power analysis was performed. The measurements were made in 20 FAI hips (FAI group) and 23 asymptomatic normal hips (ANH group). Cutoff values were evaluated using receiver operating characteristic curves. RESULTS: The mean ß-angles of the FAI and ANH groups at R0, R15, R30, R45, R60, R75, and R90° were, respectively, 73.6° and 84.2°, 66.0° and 79.3°, 57.2° and 69.2°, 48.1° and 63.1°, 46.7° and 62.5°, 50.0° and 63.7°, and 53.7° and 65.9°. For all slices, the ß-angle was significantly smaller in the FAI group than the ANH group. The optimal ß-angle cutoff values for diagnosing FAI at R0, R15, R30, R45, R60, R75, and R90 were 73.9°, 70.2°, 61.4°, 55.7°, 53.6°, 59.4°, and 60.9°, respectively. The respective specificities and sensitivities of the cutoff values at R0, R15, R30, R45, R60, R75, and R90 were 78.3% and 65.0%, 82.6% and 70.0%, 73.9% and 60.0%, 73.9% and 75.0%, 95.7% and 75.0%, 69.6% and 95.0%, and 78.3% and 80.0%. CONCLUSIONS: In all radial slices, the ß-angle was significantly smaller in the hips with symptomatic FAI than in the asymptomatic normal hips. The most useful cutoff value for diagnosing FAI was a ß-angle of 53.6° at R60.

Is the ischiofemoral space value of Japanese hip joints equal to that of Western populations?

Ischiofemoral space (IFS) is a radiological parameter employed for diagnosing ischiofemoral impingement (IFI). The mean IFS value measured with the leg in natural resting position has been reported as 23.0 mm in males and 18.6 mm in females in a patients-based Western population. The normal value of IFS for an Asian population is unknown. This study therefore aimed to investigate whether the IFS value in Japanese hip joints equals that of the Western population. We retrospectively examined 89 consecutive Japanese individuals (178 hips) (46 male subjects with 92 hips, 43 female subjects with 86 hips; mean age 58.7 ± 15.7 years, range 17-84 years) who had undergone computed tomography (CT) for conditions unrelated to hip disorders and ordered by other departments at our institution. All CT scans were performed in a standardized fashion: patient in a flat spine position, hips and knees in extension, and the leg in its natural resting position. IFS was evaluated on axial images as the shortest distance between the ischium and the lesser trochanter. The mean IFSs of this Japanese patient-based population were 20.5 ± 7.3 mm [95% confidence interval (CI) 19.0-22.0] in the male cohort and 13.9 ± 6.5 mm (95% CI 12.6-15.3) in the female cohort. The IFS value was significantly smaller in female subjects than in male subjects. Taking the lower limit of 95% CI into consideration, the IFSs measured in natural leg-resting position in the Japanese male and female groups were significantly smaller than those of the Western populations.

P2X7 ionotropic receptor is functionally expressed in rabbit articular chondrocytes and mediates extracellular ATP cytotoxicity.

Extracellular ATP regulates various cellular functions by engaging multiple subtypes of P2 purinergic receptors. In many cell types, the ionotropic P2X7 receptor mediates pathological events such as inflammation and cell death. However, the importance of this receptor in chondrocytes remains largely unexplored. Here, we report the functional identification of P2X7 receptor in articular chondrocytes and investigate the involvement of P2X7 receptors in ATP-induced cytotoxicity. Chondrocytes were isolated from rabbit articular cartilage, and P2X7 receptor currents were examined using the whole-cell patch-clamp technique. ATP-induced cytotoxicity was evaluated by measuring caspase-3/7 activity, lactate dehydrogenase (LDH) leakage, and prostagrandin E2 (PGE2) release using microscopic and fluorimetric/colorimetric evaluation. Extracellular ATP readily evoked a cationic current without obvious desensitization. This ATP-activated current was dose related, but required millimolar concentrations. A more potent P2X7 receptor agonist, BzATP, also activated this current but at 100-fold lower concentrations. ATP-induced currents were largely abolished by selective P2X7 antagonists, suggesting a predominant role for the P2X7 receptor. RT-PCR confirmed the presence of P2X7 in chondrocytes. Heterologous expression of a rabbit P2X7 clone successfully reproduced the ATP-induced current. Exposure of chondrocytes to ATP increased caspase-3/7 activities, an effect that was totally abrogated by P2X7 receptor antagonists. Extracellular ATP also enhanced LDH release, which was partially attenuated by the P2X7 inhibitor. The P2X7 receptor-mediated elevation in apoptotic caspase signaling was accompanied by increased PGE2 release and was attenuated by inhibition of either phospholipase A2 or cyclooxygenase-2. This study provides direct evidence for the presence of functional P2X7 receptors in articular chondrocytes. Our results suggest that the P2X7 receptor is a potential therapeutic target in chondrocyte death associated with cartilage injury and disorders including osteoarthritis.

Wnt signaling pathway correlates with ossification of the spinal ligament: A microRNA array and immunohistochemical study.

BACKGROUND: Ossification of the posterior longitudinal ligament or the ligamentum flavum parallels endochondral ossification. Cell differentiation at the ossification front is known to be important during this process, although the factors regulating its initiation and progression are still unclear. The purpose of this study was to identify factors important for the regulation of chondrocyte/osteoblast differentiation during spinal ossification. METHODS: Ligamentum flavum tissue was isolated from 25 patients who underwent decompressive surgery for cervical ossification of the posterior longitudinal ligament. Tissue sections were used for in vitro culture to obtain primary cells through migration methods. To identify microRNAs associated with ossification of the posterior longitudinal ligament, cultured cells were prepared from the ligamentous tissue (n = 4; continuous type) or from control ligamentous samples harvested from patients with cervical spondylosis without spinal ossification, and analyzed using a microRNA array. The ligamentous sections were also examined by immunohistochemistry for the expression of candidate microRNA target genes. RESULTS: The microRNA array identified 177 factors; 12 of which were expressed at significantly different levels in patients with ossification of the posterior longitudinal ligament compared to those in control patients. The hsa-miR-487b-3p was down-regulated in patients with ossification of the posterior longitudinal ligament, which met the false discovery rate of <0.05. This microRNA was predicted to regulate the expression of genes involved in Wnt signaling. Furthermore, immunohistochemistry of Wnt signaling proteins, including Wnt 3a, LRP5/6, and beta-catenin, revealed positive expression in mesenchymal cells and/or premature chondrocytes at the ossification front. CONCLUSION: Our results suggested that down-regulation of miR-487b-3p plays an important role in the initiation of Wnt signaling during the ossification process. Wnt signaling may regulate both chondrocyte and osteoblast differentiation and the specification of endochondral ossification in the pathogenesis of ossification of the posterior longitudinal ligament or the ligamentum flavum.

Total knee arthroplasty for treatment of osteoarthritis with prolonged patellar dislocation.

Prolonged dislocation of the patella is a rare condition and is often related to severe osteoarthritis (OA) of the femorotibial (FT) joint. For this condition's treatment, numerous surgical techniques using total knee arthroplasty (TKA) have been published. To the best of our knowledge, this case report is the first description of the use of lateral release alone to treat recurrent patellar subluxation with TKA. An interesting point in this case is that the patient had a good recovery after TKA in spite of quite a long-term (a duration of almost 55 years) dislocation of her patella and development of secondary OA. We describe a case that we treated by TKA for FT-OA with a prolonged patellar dislocation. We were able to obtain good patellar reduction without additional surgery by performing adequate lateral release of the patellar retinaculum. This clinical case indicates the usefulness of lateral patellar retinaculum release for obtaining stable patellar tracking in TKA for FT-OA with remaining lateral patellar dislocation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Evaluation of the quality of CT images acquired with the single energy metal artifact reduction (SEMAR) algorithm in patients with hip and dental prostheses and aneurysm embolization coils.

PURPOSE: We compared the quality of the images acquired with single energy metal artifact reduction (SEMAR) on CT scans of three different human body areas. MATERIALS AND METHODS: Our institutional review board approved the study protocol. CT studies of 58 patients (hip prosthesis, n = 20; iliac artery aneurysm embolization, n = 20; dental prosthesis, n = 18) were retrospectively reconstructed using interactive reconstruction (IR) and IR plus SEMAR. Two radiologists independently evaluated the images for the reduction of metal artifacts at three sites, i.e., 0-1, 1-5, and 5-10 cm from their edges, and recorded their findings on a 100-mm-long line that corresponded to the Likert scale and ranged from 0 (invisible) to 100 mm (clearly visible). The standard deviation in Hounsfield units was used as the noise assessment tool. Statistical analysis was performed with the t test and the Wilcoxon signed-rank test. RESULTS: The image quality of scans of hip prostheses and metal embolization coils was significantly improved when SEMAR was used (p < 0.05). On scans of dental prostheses, SEMAR did not contribute significantly, especially in the area 1 cm from the edge of the implant. CONCLUSION: Visual subjective evaluation showed that SEMAR improved the image quality.

The COX-2 selective blocker etodolac inhibits TNFα-induced apoptosis in isolated rabbit articular chondrocytes.

Chondrocyte apoptosis contributes to the disruption of cartilage integrity in osteoarthritis (OA). Recently, we reported that activation of volume-sensitive Cl- current (ICl,vol) mediates cell shrinkage, triggering apoptosis in rabbit articular chondrocytes. A cyclooxygenase (COX) blocker is frequently used for the treatment of OA. In the present study, we examined in vitro effects of selective blockers of COX on the TNFα-induced activation of ICl,vol in rabbit chondrocytes using the patch-clamp technique. Exposure of isolated chondrocytes to TNFα resulted in an obvious increase in membrane Cl- conductance. The TNFα-evoked Cl- current exhibited electrophysiological and pharmacological properties similar to those of ICl,vol. Pretreatment of cells with selective COX-2 blocker etodolac markedly inhibited ICl,vol activation by TNFα as well as subsequent apoptotic events such as apoptotic cell volume decrease (AVD) and elevation of caspase-3/7 activity. In contrast, a COX-1 blocker had no effect on the decrease in cell volume or the increase in caspase-3/7 activity induced by TNFα. Thus, the COX-2-selective blocker had an inhibitory effect on TNFα-induced apoptotic events, which suggests that this drug would have efficacy for the treatment of OA.

17ß-Oestradiol inhibits doxorubicin-induced apoptosis via block of the volume-sensitive Cl(-) current in rabbit articular chondrocytes.

BACKGROUND AND PURPOSE Chondrocyte apoptosis contributes to disruption of cartilage integrity in osteoarthritis. Recent evidence suggested that the volume-sensitive organic osmolyte/anion channel [volume-sensitive (outwardly rectifying) Cl(-) current (I(Cl,vol) )] plays a functional role in the development of cell shrinkage associated with apoptosis (apoptotic volume decrease) in several cell types. In this study, we investigated the cellular effects of 17ß-oestradiol on doxorubicin-induced apoptotic responses in rabbit articular chondrocytes. EXPERIMENTAL APPROACH Whole-cell membrane currents and cross-sectional area were measured from chondrocytes using a patch-clamp method and microscopic cell imaging, respectively. Caspase-3/7 activity was assayed as an index of apoptosis. KEY RESULTS Addition of doxorubicin (1 µM) to isosmotic bath solution rapidly activated the Cl(-) current with properties similar to those of I(Cl,vol) in chondrocytes. Doxorubicin also gradually decreased the cross-sectional area of chondrocytes, followed by enhanced caspase-3/7 activity; both of these responses were totally abolished by the I(Cl,vol) blocker DCPIB (20 µM). Pretreatment of chondrocytes with 17ß-oestradiol (1 nM) for short (approximately 10 min) and long (24 h) periods almost completely prevented the doxorubicin-induced activation of I(Cl,vol) and subsequent elevation of caspase-3/7 activity. These effects of 17ß-oestradiol were significantly attenuated by the oestrogen receptor blocker ICI 182780 (10 µM), as well as the phosphatidyl inositol-3-kinase (PI3K) inhibitors wortmannin (100 nM) and LY294002 (20 µM). Testosterone (10 nM) had no effect on the doxorubicin-induced Cl(-) current. CONCLUSIONS AND IMPLICATIONS 17ß-Oestradiol prevents the doxorubicin-induced cell shrinkage mediated through activation of I(Cl,vol) and subsequent induction of apoptosis signals, through a membrane receptor-dependent PI3K pathway in rabbit articular chondrocytes.

Spatiotemporal control of proliferation and differentiation of bone marrow-derived mesenchymal stem cells recruited using collagen hydrogel for repair of articular cartilage defects.

Articular cartilage has a poor healing capacity, and cartilage regeneration is not always warranted to achieve healing. On the other hand, collagen scaffolds have been shown to support regeneration of articular cartilage defects in animal models, whereas bone morphogenetic protein-2 (BMP-2) is known to cause chondrogenic differentiation of marrow-derived mesenchymal stem cells (MSCs). The purpose of this study was to evaluate the effectiveness of intra-articular administration of BMP-2 into bone marrow-derived MSCs recruited to defects using original collagen hydrogel in rabbits at various time points. Full-thickness defects were created in both knees, then collagen hydrogels were transplanted, and BMP-2 was supplied for 1-week periods, as follows. BMP-2 was administered immediately after the operation for 1 week (BMP0-1 group), and BMP-2 was administered between weeks 1 and 2 after the operation (BMP1-2 group). BMP2 was administered between weeks 2 and 3 (BMP2-3 group). Specimens were then obtained, and bromodeoxyuridine (BrdU)-positive cells were enumerated and histologic grading was also performed. In addition, the gene expression analysis was performed using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) assays. Enumeration of BrdU-positive cells showed a significant increase in the BMP0-1 group compared with the other groups. Similarly, histologic scores in the BMP0-1 group were superior for up to 8 weeks. Finally, RT-PCR findings revealed that immediate BMP-2 administration enhanced chondrogenic differentiation.

Regulatory role of tyrosine phosphorylation in the swelling-activated chloride current in isolated rabbit articular chondrocytes.

Articular chondrocytes are exposed in vivo to the continually changing osmotic environment and thus require volume regulatory mechanisms. The present study was designed to investigate (i) the functional role of the swelling-activated Cl(-) current (I(Cl,swell)) in the regulatory volume decrease (RVD) and (ii) the regulatory role of tyrosine phosphorylation in I(Cl,swell), in isolated rabbit articular chondrocytes. Whole-cell membrane currents were recorded from chondrocytes in isosmotic, hyposmotic and hyperosmotic external solutions under conditions where Na(+), K(+) and Ca(2+) currents were minimized. The cell surface area was also measured using microscope images from a separate set of chondrocytes and was used as an index of cell volume. The isolated chondrocytes exhibited a RVD during sustained exposure to hyposmotic solution, which was mostly inhibited by the I(Cl,swell) blocker 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl)oxobutyric acid (DCPIB) at 20 microM. Exposure to a hyposmotic solution activated I(Cl,swell), which was also largely inhibited by 20 microM DCPIB. I(Cl,swell) in rabbit articular chondrocytes had a relative taurine permeability (P(tau)/P(Cl)) of 0.21. Activation of I(Cl,swell) was significantly reduced by the protein tyrosine kinase (PTK) inhibitor genistein (30 microM) but was only weakly affected by its inactive analogue daidzein (30 microM). Intracellular application of protein tyrosine phosphatase (PTP) inhibitor sodium orthovanadate (250 and 500 microM) resulted in a gradual activation of a Cl(-) current even in isosmotic solutions. This Cl(-) current was almost completely inhibited by 4,4-diisothiocyanatostilbene-2,2-disulfonate (DIDS, 500 microM) and was also largely suppressed by exposure to hyperosmotic solution, thus indicating a close similarity to I(Cl,swell). Pretreatment of chondrocytes with genistein significantly prevented the activation of the Cl(-) current by sodium orthovanadate, suggesting that the basal activity of endogenous PTK is required for the activation of this Cl(-) current. Our results provide evidence to indicate that activation of I(Cl,swell) is involved in RVD in isolated rabbit articular chondrocytes and is facilitated by tyrosine phosphorylation.

Swelling-activated Cl(-) current in isolated rabbit articular chondrocytes: inhibition by arachidonic Acid.

Articular chondrocytes play an important role in maintaining the structure and function of the cartilage in synovial joints, which is closely influenced by mechanical or osmotic stress. In the present study, isolated rabbit articular chondrocytes were examined during hyposmotic stress using the whole-cell patch-clamp method. When exposed to hyposmotic external solutions (approximately 5% or 32% decrease in osmolarity), isolated rabbit articular chondrocytes exhibited hyposmotic cell swelling, accompanied by the activation of the swelling-activated Cl(-) current (I(Cl,swell)). I(Cl,swell) was practically time-independent at potentials negative to +50 mV but exhibited rapid inactivation at more positive potentials. I(Cl,swell) was potently inhibited by the Cl(-) channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid, glibenclamide, and tamoxifen, but was little affected by pimozide. I(Cl,swell) was also found to be acutely inhibited by arachidonic acid in a concentration-dependent manner with an IC50 of 0.81 microM. The maximal effect (approximately 100% block) was obtained with 10 microM arachidonic acid. The arachidonic acid metabolites prostaglandin E(2), leukotriene B(4), and leukotriene D(4) had no appreciable effect on IC(l,swell), suggesting that the inhibitory effect of arachidonic acid did not require its metabolism. The present study thus reveals the presence of I(Cl,swell) in rabbit articular chondrocytes that exhibits high sensitivity to direct inhibition by arachidonic acid.