A Retrospective Comparison of Clinical Efficacy between Multimodal Analgesia and Patient-Controlled Epidural Analgesia in Patients Undergoing Total Knee Arthroplasty.

Background and Objectives: Adequate pain management during early rehabilitation is mandatory for improving the outcomes of patients undergoing total knee arthroplasty (TKA). Conventional pain management, mainly comprising opioids and epidural analgesia, may result in certain adverse effects such as dizziness, nausea, and motor blockade. We proposed a multimodal analgesic (MA) strategy involving the use of peripheral nerve block (NB), periarticular injection (PAI), and intravenous patient-controlled analgesia (IVPCA). This study compared the clinical efficacy and adverse effects of the proposed MA strategy and patient-controlled epidural analgesia (PCEA). Materials and Methods: We enrolled 118 patients who underwent TKA under spinal anesthesia. The patients followed either the MA protocol or received PCEA after surgery. The analgesic effect was examined using a numerical rating scale (NRS). The adverse effects experienced by the patients were recorded. Results: A lower proportion of patients in the MA group experienced motor blockade (6.45% vs. 22.98%) compared to those in the PCEA group on the first postoperative day. Furthermore, a lower proportion of patients in the MA group experienced numbness (18.52% vs. 43.33%) than those in the PCEA group on the first postoperative day. Conclusions: The MA strategy can be recommended for reducing the occurrence of motor blockade and numbness in patients following TKA. Therefore, the MA strategy ensures early rehabilitation while maintaining adequate pain relief.

Validation and modification of the Coronal Plane Alignment of the Knee classification in the Asian population.

AIMS: The Coronal Plane Alignment of the Knee (CPAK) classification is a simple and comprehensive system for predicting pre-arthritic knee alignment. However, when the CPAK classification is applied in the Asian population, which is characterized by more varus and wider distribution in lower limb alignment, modifications in the boundaries of arithmetic hip-knee-ankle angle (aHKA) and joint line obliquity (JLO) should be considered. The purposes of this study were as follows: first, to propose a modified CPAK classification based on the actual joint line obliquity (aJLO) and wider range of aHKA in the Asian population; second, to test this classification in a cohort of Asians with healthy knees; third, to propose individualized alignment targets for different CPAK types in kinematically aligned (KA) total knee arthroplasty (TKA). METHODS: The CPAK classification was modified by changing the neutral boundaries of aHKA to 0° ± 3° and using aJLO as a new variable. Radiological analysis of 214 healthy knees in 214 Asian individuals was used to assess the distribution and mean value of alignment angles of each phenotype among different classifications based on the coronal plane. Individualized alignment targets were set according to the mean lateral distal femoral angle (LDFA) and medial proximal tibial angle (MPTA) of different knee types. RESULTS: A very high concentration, 191 from 214 individuals (89.3%), were found in knee types with apex distal JLO when the CPAK classification was applied in the Asian population. By using aJLO as a new variable, the high distribution percentage in knee types with apex distal JLO decreased to 125 from 214 individuals (58.4%). The most common types in order were Type II (n = 70; 32.7%), Type V (n = 55; 25.7%), and Type I (n = 46; 21.5%) in the modified CPAK classification. CONCLUSION: The modified CPAK classification corrected the uneven distribution when applying the CPAK classification in the Asian population. Setting individualized TKA alignment targets according to CPAK type may be a practical method to recreate optimal LDFA and MPTA in KA-TKA. Cite this article: Bone Jt Open 2022;3(3):211-217.

Total knee arthroplasty according to the original knee phenotypes with kinematic alignment surgical technique-early clinical and functional outcomes.

BACKGROUND: The kinematic alignment (KA) technique in total knee arthroplasty (TKA) aims to restore the native alignment of pre-disease knee joint anatomy. Determining the individualized alignment targets is crucial for pre-operative planning, which can be set according to different original knee phenotypes. Five most common knee phenotypes have been categorized for KA-TKA alignment target setting in our previous study. The purpose of this study was to investigate the distribution of the five phenotypes in advanced OA knee patients and evaluate the clinical outcomes of this phenotype-oriented KA-TKA using the generic instrument, with particular emphasis on alignment strategy, surgical technique, survivorship, radiographic and functional outcomes. METHODS: The clinical data of 123 patients (88 women, 35 men) who had undergone 140 TKAs in our hospital were reviewed. All the TKAs were performed with alignment targets set according to the original phenotypes of the knee, with the KA method, using the generic total knee instrument. The patients' demographics, preoperative and postoperative knee alignment angles, one-year postoperative range of motion (ROM), Oxford knee scores (OKS), Combined knee society score (CKSS) were collected and analyzed. RESULTS: The 3 years survivorship was 99.3% for all cause of revision, and 100% with revision other than infection as the endpoint. The preoperative phenotypes of the knee were as follows: neutral alignment 20.1% (type 1: 3.6%, type 2: 16.5%), varus alignment 71.2% (type 3: 46.0%, type 4: 25.2%), and valgus alignment (type 5: 8.6%). Using our protocol, patients with different knee phenotypes could get similar great functional improvement though the postoperative alignment parameters were significantly different between the knee phenotypes (P < 0.05). CONCLUSION: The early outcomes of this phenotype-oriented KA-TKA using generic total knee instruments are promising. Setting individualized alignment target according to original knee phenotype is rational and practical. The residual varus alignment did not cause any aseptic loosening in the 3 years follow-up. Long-term survivorship and functional outcomes need to be evaluated in future studies.

Posterior cruciate ligament reconstruction implemented by the Ligament Advanced Reinforcement System over a minimum follow-up of 10 years.

PURPOSE: This study evaluated the long-term clinical follow-up results of patients who underwent double-bundle posterior cruciate ligament (PCL) reconstruction using the Ligament Advanced Reinforcement System (LARS). METHODS: Patients were assessed using clinical scores that included the Tegner activity level scale, the Lysholm score, and the International Knee Documentation Committee (IKDC) score. KT-1000 was adopted to assess stability. Radiographs and magnetic resonance imaging (MRI) were used to evaluate osteoarthritis and LARS condition. RESULTS: This study examined 38 patients, of which follow-up procedures were completed for 33 patients, resulting in a follow-up rate of 86.8%. The average follow-up period was 11.9 ±â€¯1.2 years (range: 10.3-14.2 years). The median scores of the clinical scales were as follows: Tegner activity score, 6 (range: five to seven); Lysholm score, 90 (range: 67-100); and IKDC score, 89.7 (range: 46-100). The median of the side-to-side difference (SSD) was four millimeters (range: 0-10 mm). In radiographs, the moderate OA rate was 6.9%. MRI results revealed that 26 patients exhibited ingrowth and 11 patients exhibited partial rupture of the LARS. With SSD ≤ 3 mm set as the standard for successful knee stabilization, the optimal cutoff point of LARS midsubstance thickness in the receiver operating characteristic (ROC) curve analysis was 14.3 mm. CONCLUSIONS: Long-term follow-up of the studied patients demonstrated the durability of LARS. However, clinical outcomes showed no enhancement using LARS, so it is not recommended for routine use in PCL reconstruction. LEVEL OF EVIDENCE: IV.

Activity-related outcome in anterior cruciate ligament reconstruction with synthetic ligament advanced reinforcement system.

BACKGROUND: Arthroscopic anterior cruciate ligament (ACL) reconstruction with ligament advanced reinforcement system (LARS) had revealed good results with low complication and failure rate in series of studies. The specific candidates for ACL reconstruction with LARS are still unknown anyway. The purpose of this study is to evaluate the activity-related outcome in ACL reconstruction using LARS ligament. METHODS: A total of 43 unilateral arthroscopic ACL reconstructions with LARS were collected and divided into two groups: group A (preinjury Tegner score ≥ 6, n = 20) and group B (preinjury Tegner score < 6, n = 23). We had analyzed the stability of knee and functional outcome with a minimum of 2-years follow up. RESULTS: All patients were aware of improvement over the knee stability immediately after ACL reconstruction with LARS. The functional outcome of knee was improved in both groups by analysis with the Lysholm score and modified International Knee Documentation Committee (IKDC) score. The postoperative grading of the knee examination form of modified IKDC grade showed no statistical difference in both groups. CONCLUSION: Arthroscopic ACL reconstruction with LARS was encouraged as an alternative option even in high sports demand patients.

Comparison of Total Joint Replacement Rate Between Patients With Hemophilia A and Patients With Hemophilia B: A Population-Based and Retrospective Cohort Study.

Recurrent hemarthrosis in patients with hemophilia (PWH) results in chronic arthropathy requiring total joint replacement (TJR). This study aimed to compare the difference in TJR rate between patients with hemophilia A (HA) and hemophilia B (HB). A final total of 935 PWH (782 HA and 153 HB) without inhibitors were collected from the Taiwan's National Health Insurance Research Database between 1997 and 2013. Demographics, clinical characteristics, and TJR rate were compared between the 2 groups. The annual use of clotting factor concentrate was not different between HA and HB groups (P = .116). The rate of comorbidities except for 29 PWH having HIV who were all in the HA group was also not different between the 2 groups. A total of 99 (10.6%) PWH had undergone 142 TJR procedures during the study period. All of them had received on-demand therapy. No difference was found in the cumulative incidence of TJR between HA and HB (P = .787). After adjusting for various confounders including age, pyogenic arthritis, and HIV infection, no increased risk of TJR was found in patients with HA versus Patients with HB (hazard ratio: 0.92, 95% confidence interval 0.54-1.58). This finding suggests that the rate of TJR between patients with HA and HB is not significantly different.

Outcome of perioperative hemostatic management in patients with hemophilia without inhibitors undergoing 161 invasive or surgical procedures.

Perioperative management of persons with hemophilia (PWH) is a challenge for surgeons and hematologists. Reductions in mortality rate and complications have been achieved since the introduction of clotting factor concentrates (CFCs), which improve hemostatic control. However, there is no clear consensus on the optimal dosing of CFC administration. The aim of this study was to evaluate the outcome of PWH without inhibitors in patients undergoing invasive or surgical procedures. A total of 161 procedures, including 57 major and 104 minor ones were retrospectively reviewed. The characteristics of PWH, age at procedure, duration and total amount of CFC administration during the perioperative period, hemostatic adequacy, and complications were summarized. The study showed a low rate of bleeding (1.2%), infection (0%), thromboembolic event (0%), and inhibitor development (0%). The results revealed the doses and duration of CFC administration for several major and minor procedures which were capable of achieving excellent hemostatic control.

Integrated risk scoring model for predicting dynamic hip screw treatment outcome of intertrochanteric fracture.

BACKGROUND: Dynamic hip screw (DHS) is a common device for treating intertrochanteric fracture (ITF). Various risk factors have been reported to be associated with the operative treatment outcome. However, an integrated risk scoring prediction model is lacking. In this study, we aimed to develop a prediction model for treatment outcome of intertrochanteric fracture. METHODS: We analyzed 442 AO/OTA 31-A1 and A2 fractures which were treated with DHS during the period January 2000 to June 2014 in a level I trauma center. Risk factors including age, gender, injured side, lag screw position, AO/OTA classification, tip-apex distance, postoperative lateral wall fracture, reduction patterns were analyzed to determine their influence on treatment outcome. Integrated risk scores of significant predictors were used to construct a prediction model. RESULTS: AO/OTA 31-A2 classification, postoperative lateral wall fracture, posteriorly inserted lag screw and varus reduction pattern were significant risk predictors for DHS failure. The failure risk for low- and high-risk groups were significantly different (P<0.001) CONCLUSION: AO/OTA 31-A2 classification, postoperative lateral wall fracture, posteriorly inserted lag screw and varus reduction pattern were significant risk predictors for DHS failure. We developed a model that integrates these factors to predict the treatment outcome, which had excellent prediction accuracy and discriminatory ability. The models may provide useful information for orthopedic doctors to identify patients who need early intervention as well as ITF patients who require more frequent follow-up in the postoperative period.

Single-blinded, randomised preliminary study evaluating the effects of 2†Hz electroacupuncture for postoperative pain in patients with total knee arthroplasty.

OBJECTIVE: To explore the point-specific clinical effect of 2 Hz electroacupuncture (EA) in treating postoperative pain in patients undergoing total knee arthroplasty (TKA), METHODS: In a randomised, partially single-blinded preliminary study, 47patients with TKA were randomly divided into three groups: control group (CG, n=17) using only patient-controlled analgesia (PCA); EA group (EAG, n=16) with 2 Hz EA applied at ST36 (Zusanli) and GB34 (Yanglingquan) contralateral to the operated leg for 30 min on the first two postoperative days, also receiving PCA; and non-point group (NPG, n=14), with EA identical to the EAG except given 1 cm lateral to both ST36 and GB34. The Mann-Whitney test was used to show the difference between two groups and the Kruskal-Wallis test to show the difference between the three groups. RESULTS: The time until patients first required PCA in the CG was 34.1±22.0 min, which was significantly shorter than the 92.0±82.7 min in the EAG (p<0.001) and 90.7±94.8 min in the NPG (p<0.001); there was no difference between the EAG and NPG groups (p>0.05). The total dosage of PCA solution given was 4.6±0.9 mL/kg body weight in the CG, 4.2±1.0 mL/kg in the EAG and 4.5±1.0 mL/kg in the NPG; there were no significant differences (p>0.05) among the three groups. CONCLUSIONS: In this small preliminary study, EA retarded the first demand for PCA in comparison with no EA. No effect was seen on the total dosage of PCA required and no point-specific effect was seen.

Incidence and survival of cancers among 1,054 hemophilia patients: A nationwide and 14-year cohort study.

As life expectancy increases in persons with hemophilia (PWH), more age-related diseases such as cancer emerge among this patient group. The aim of this study was to investigate incidence and survival of cancers among PWH in Taiwan. We analyzed data of 1,054 PWH retrieved from Taiwan's National Health Insurance Research Database between 1997 and 2010, by comparing variables to 10540 age- and gender-matched healthy individuals from the general population. There were 43 PWH and 178 individuals of general population with newly diagnosed cancer (RR 2.42, 95% CI 1.74-3.35). The cumulative incidences of cancer in PWH and the general population were 4.7 and 1.9%, respectively. Hepatocellular carcinoma (HCC) was the major type of cancer (17 cases) in PWH; cancer rate was still increased when HCC and HIV-related cancers were excluded (RR 1.66, 95% CI 1.06-2.59). There was no significant difference observed in lung, colorectal, or prostate cancer occurrence. Compared to the general population, PWH were younger at the time of cancer diagnosis (45.1 vs. 57.2 years old, P value < 0.001), and had fewer co-morbidities. Nineteen PWH with cancers died during the study period, and no bleeding-related death was recorded among these patients. The survival rate was not different between PWH and the general population, P = 0.86. In conclusion, the cumulative incidence of cancer among PWH was higher than the general population. PWH with cancer were younger and had fewer comorbidities, but the survival rates were similar in the two groups.

Prevalence and risk factors of atherothrombotic events among 1054 hemophilia patients: a population-based analysis.

INTRODUCTION: Reports on the prevalence and risk factors of atherothrombotic events (AEs) are conflicting in persons with hemophilia (PWH). METHODS: This study evaluated the prevalence and risk factors of AEs among 1054 male hemophilia patients, using data collected from Taiwan's National Health Insurance Research Database between 1997 and 2010, by comparing variable to those of an unaffected 10540 age- and gender-matched general population. RESULTS: The proportions of all AEs among PWH, including 26 ischemic stroke, 29 coronary artery disease and 5 peripheral arterial disease were comparable to those in the general population. The mean age at diagnosis of AE among PWH was younger than that in the general population: 49.0 (95% CI, 43.6-54.5) and 55.8 years (95% CI, 54.5-57.0), P = 0.019, respectively. PWH with Chronic Obstructive Pulmonary Disease (COPD), hypertension, and hyperlipidemia were associated with greater risk for the occurrence of AEs, with hazard ratios (95% CI) of 3.42 (1.25-9.38), 4.15 (2.11-8.17), and 2.84 (1.39-5.79), respectively. PWH who needed replacement therapy had a lower risk of AEs than those who did not need, with a hazard ratio (95% CI) of 0.41 (0.21-0.81). CONCLUSIONS: The study indicated the prevalence of AEs among PWH was comparable to that of the general population. AEs appeared at an earlier age among PWH. COPD, hypertension, and hyperlipidemia were risk factors for AEs. PWH who needed replacement therapy may have a lower risk of AEs.

Evaluation of methods and timing in nail dynamisation for treating delayed healing femoral shaft fractures.

INTRODUCTION: Dynamisation is a simple method for treating femoral shaft fractures (FSFs) in patients with delayed healing after intramedullary nailing. However, only around half of patients with a slow-healing FSF have been successfully treated with this strategy. Although it is thought that dynamisation with a screw preserved in the dynamic locking hole improves treatment outcome in these patients, to date, no studies have demonstrated empirical evidence supporting this technique. In this study, we investigated the effects of dynamisation with and without rotation and length control as well as timing of dynamisation on treatment outcomes in FSF patients with delayed healing. PATIENTS AND METHODS: Thirty-nine consecutive acute FSF patients with static locking intramedullary nails who subsequently underwent dynamisation were recruited between January 2000 and June 2011. The indication for dynamisation was the presence of gap caused by bone absorption or over-traction at the fracture site when the locking screws were placed. Age, gender, dynamisation method, fracture classification, duration from nail insertion to dynamisation (i.e., timing of dynamisation) and dynamisation outcome were included in the statistical analysis. RESULTS: Patients whose nail was dynamised with a screw preserved in the dynamic locking hole had a significantly higher successful bone union rate (14/15 vs. 14/24, p=0.028) compared with those with all screws removed from one end of the nail. The patients treated in 10-24 weeks had a significantly increased chance of bone union than those treated after 24 weeks (p=0.027). A significantly higher bone union rate (p=0.036) was observed in 10-24 weeks (83.3%) than after 24 weeks (33.3%) in the group of dynamisation with all screws removed from one end of the nail. No statistical difference in bone union success rate was found between patients at 10-24 weeks and after 24 weeks in the group of dynamisation with a screw preserved in the dynamic locking hole. There were no significant differences in outcome based on other variables. CONCLUSION: (1) Dynamisation with a screw preserved in the dynamic locking hole was associated with a higher success rate in bone union than all screws removed from one end of the nail for patients with delayed healing FSFs. (2) Early dynamisation (10-24 weeks) had a better outcome than late dynamisation (>24 weeks). Late dynamisation with all screws removed from one end of the nails resulted in a poor success rate. Alternative treatment should be considered if the latter approach is to be adopted.

Outcomes of arthroscopic double-bundle PCL reconstruction using the LARS artificial ligament.

The purpose of this study was to assess the outcomes of posterior cruciate ligament (PCL) reconstruction using the Ligament Augmentation and Reconstruction System (LARS) (JK Orthomedic Ltd, Dollard-des-Ormeaux, Quebec, Canada) artificial ligament. Compared with older artificial ligaments, the LARS, which has been used in Europe for 15 years, is more resistant to wear and tear, has satisfactory torsional fatigue resistance, and has good biocompatibility. The current is study included 38 double-bundle PCL reconstructions using the LARS artificial ligament in 38 patients. Mean patient age was 32.6 years, and mean time from injury to surgery was 6 months. Mean follow-up was 37 months (range, 30-68 months). The study endpoint was 2-year follow-up. Mean Tegner score improved from 3.4 ± 0.6 preoperatively to 6.0 ± 1.4 postoperatively (P<.001), and mean Lysholm score improved from 70.0 ± 11.0 pre-operatively to 91.7 ± 5.5 postoperatively (P<.001). Knee laxity decreased significantly postoperatively (P<.001), and no differences existed at 1- and 2-year follow-up. After surgery using the Y-type LARS artificial ligament, knee function and stability improved. Using the LARS artificial ligament for double-bundle reconstruction of the PCL avoids donor-site morbidity and disease transmission. The complication rate is low, and the results appear to be stable with time and comparable with those obtained with other grafts. Double-bundle PCL reconstruction with the LARS artificial ligament may be an alternative treatment option.

Adiponectin increases MMP-3 expression in human chondrocytes through AdipoR1 signaling pathway.

Articular adipose tissue is a ubiquitous component of human joints, and adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and involved in energy homeostasis. The adiponectin is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinases (MMP)-3 may contribute to the breakdown of articular cartilage during arthritis. We investigated the signaling pathway involved in MMP-3 caused by adiponectin in human chondrocytes. Adiponectin increased the secretion of MMP-3 in cultured human chondrocytes, as shown by qPCR, Western blot, and ELISA analysis. Adiponectin-mediated MMP-3 expression was attenuated by AdipoR1 but not AdipoR2 siRNA. Pretreatment with 5'-AMP-activated protein kinase (AMPK) inhibitor (araA and compound C), p38 inhibitor (SB203580), and NF-κB inhibitor (PDTC and TPCK) also inhibited the potentiating action of adiponectin. Activations of p38, AMPK, and NF-κB pathways after adiponectin treatment were demonstrated. Taken together, our results provide evidence that adiponectin acts through AdipoR1 to activate p38 and AMPK, resulting in the activations of NF-κB on the MMP-3 promoter and contribute cartilage destruction during arthritis.

Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway.

Peptidoglycan (PGN), the major component of the cell wall of Gram-positive bacteria, activates the innate immune system of the host and induces the release of cytokines and chemokines. We investigated the signaling pathway involved in IL-6 production stimulated by PGN in rheumatoid arthritis synovial fibroblasts. PGN caused concentration- and time-dependent increases in IL-6 production. PGN-mediated IL-6 production was attenuated by TLR2 small interfering RNA and nucleotide-binding oligomerization domain 2 small interfering RNA. Pretreatment with PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor, and AP-1 inhibitor (tanshinone IIA) also inhibited the potentiating action of PGN. PGN increased the focal adhesion kinase (FAK), PI3K, and Akt phosphorylation. Stimulation of rheumatoid arthritis synovial fibroblast cells with PGN increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the IL-6 promoter. PGN mediated an increase in the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to AP-1 element was inhibited by Ly294002, Akt inhibitor, and FAK mutant. Our results suggest that PGN increased IL-6 production in human synovial fibroblasts via the TLR2 receptor/FAK/PI3K/Akt and AP-1 signaling pathway.

Involvement of AdipoR receptor in adiponectin-induced motility and alpha2beta1 integrin upregulation in human chondrosarcoma cells.

Chondrosarcoma is a type of highly malignant tumor with a capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and is involved in energy homeostasis. However, the effect of adiponectin on migration activity in human chondrosarcoma cells is mostly unknown. We found that adiponectin increased the migration and expression of alpha2beta1 integrin in human chondrosarcoma cells. The protein and messenger RNA expression of adiponectin receptor (AdipoR1 and AdipoR2) in chondrosarcoma patients and chondrosarcoma cell lines were significantly higher than the normal cartilage. Moreover, primary chondrosarcoma and chondrosarcoma cell lines (SW1353 and JJ012) were more invasive than normal chondrocytes. Adiponectin-mediated migration and integrin expression was attenuated by 5'-adenosine monophosphate-activated protein kinase (AMPK) small interfering RNA and an AMPK inhibitor (Ara A and compound C). Activation of p38 and nuclear factor-kappa B (NF-kappaB) pathways after adiponectin treatment was demonstrated, and adiponectin-induced expression of integrins and migration activity was inhibited by the specific inhibitor and mutant of p38 and NF-kappaB cascades. This study showed for the first time that adiponectin mediates the migration of human chondrosarcoma cells. One mechanism underlying adiponectin-directed migration was transcriptional upregulation of alpha2beta1 integrin and activation of AdipoR receptor, AMPK, p38 and NF-kappaB pathways.

Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts.

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-8 production caused by leptin in both rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). RASF and OASF expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-8 production. Leptin-mediated IL-8 production was attenuated by OBRl receptor antisense oligonucleotide, JAK2 inhibitor or STAT3 small interference RNA (siRNA). Transfection with insulin receptor substrate (IRS)-1 siRNA or dominant-negative mutant of p85 and Akt or pretreatment with phosphatidylinositol 3-kinase inhibitor (Ly294002 and wortmannin), Akt inhibitor, NF-kappaB inhibitor (PDTC) and NF-kappaB inhibitor peptide also inhibited the potentiating action of leptin. Stimulation of RASF with leptin activated IkappaB kinase alpha/beta (IKK alpha/beta), p65 phosphorylation at Ser(276), p65 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked IL-8 expression. The binding of p65 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 acetylation on the IL-8 promoter was enhanced by leptin, which was inhibited by wortmannin, Akt inhibitor or IRS-1 siRNA. These results suggest that leptin increased IL-8 production in synovial fibroblast via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300.