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ID PMID Title PublicationDate abstract
22715821 Downregulation of TLR-7 receptor in hepatic and non-hepatic patients with lichen planus. 2012 Jul BACKGROUND: Lichen planus (LP) is an inflammatory disease of the skin and oral mucosa. The association of LP and chronic hepatitis C virus (HCV) is well established, with variable prevalence rates among different populations. Toll-like receptors (TLRs) are key regulators of both the innate response and the adaptive response. However, TLRs also interact with endogenous ligands released by necrotic cells, and this process can intensify autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. OBJECTIVE: To investigate the role of Toll-like receptor-7 (TLR-7) in LP through the detection of TLR-7 protein, and to compare between the expression of TLR-7 protein in HCV-positive and HCV-negative patients with LP. MATERIALS AND METHODS: The study included 20 skin biopsies from patients with LP and 10 control biopsies. TLR-7 protein was detected by Western blot analysis. Detection of HCV-specific antibodies in the patient serum was done using ELISA technique. RESULTS: Our analysis revealed a significantly lower level of TLR-7 protein in all the LP skin biopsies compared with controls. The expression showed no difference between HCV-positive and HCV-negative patients. CONCLUSION: We concluded that TLR-7 abnormal expression in LP may have an impact on the pathogenesis of the disease. TLR-7 receptor and HCV relationship in patients with LP could not be confirmed by this study.
22462416 High burden of rheumatic diseases in Lebanon: a COPCORD study. 2012 Apr AIM: To estimate the prevalence of rheumatic diseases in Lebanon and to explore their distribution by geographic location, age, and gender. METHOD:   Using the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) methodology, a random sample of 3530 individuals aged 15 and above was interviewed from the six Lebanese governorates. Positive respondents were evaluated by rheumatologists using the internationally accepted classification criterion of the American College of Rheumatology for the diagnosis of rheumatic diseases. RESULTS: Prevalence rates of current and past musculoskeletal problems were 24.4% and 8.4%, respectively. Shoulder (14.3%), knee (14.2%) and back (13.6%) were the most common pain sites. Point prevalence of rheumatic diseases was 15.0%. The most frequent types of rheumatic diseases were of mechanical origin, namely soft tissue rheumatism (5.8%) and osteoarthritis (4.0%). Rheumatoid arthritis (1.0%) and spondylathropathies (0.3%) constituted the most common inflammatory diseases. Coastal areas had the lowest prevalence of all diseases except for fibromyalgia. All diseases showed an increasing prevalence pattern with age and a higher prevalence among women than men. CONCLUSION: This is the first study to give population-based estimates of rheumatic diseases in Lebanon. The high burden calls for public health attention for early detection, control and prevention of these conditions. Point prevalence of individual diseases was within the range of results from other COPCORD surveys with some variations that can be attributed to differences in methodology and geo-ethnic factors.
22451020 The effect of various disease-modifying anti-rheumatic drugs on the suppressive function o 2013 Feb Accumulating evidence suggests that defects in the function of CD4(+)CD25(+) regulatory T cells (Tregs) are important in immune-mediated diseases such as rheumatoid arthritis. Here, we investigated the effects of various disease-modifying anti-rheumatic drugs (DMARDs) on Treg function. Tregs and CD4(+)CD25(-) effector T cells (Teffs) were isolated from peripheral blood mononuclear cells obtained from healthy adults. Isolated Tregs were cultured with the DMARDs methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF), or infliximab (INF). We found that each DMARD had a different effect on Treg function. SSZ and LEF inhibited the anti-proliferative function of Tregs on cocultured Teffs and reduced Treg expression of Foxp3 mRNA, whereas MTX and INF did not.
22349611 Validated methods for assessment of subclinical atherosclerosis in rheumatology. 2012 Feb 21 Rheumatoid arthritis, as well as other types of arthritides and connective tissue diseases, is associated with accelerated atherosclerosis, and increased cardiovascular morbidity and mortality. The early signs of cardiovascular disease therefore need to be recognized in patients with these conditions so that effective cardiovascular protection can be introduced. This Review provides an overview of validated techniques that are currently available to determine subclinical atherosclerosis in patients with rheumatic conditions. Techniques for early assessment of endothelial dysfunction include brachial artery flow-mediated vasodilation and laser Doppler flowmetry. Coronary circulation can be assessed by measuring coronary flow reserve using CT, MRI or PET based techniques. The standard indicators of arterial stiffness are pulse-wave velocity and the augmentation index. Carotid atherosclerosis is determined by the common carotid intima-media thickness (ccIMT) measurement or by the assessment of plaques and plaque areas. The combination of ccIMT with plaque assessment is likely to increase the predictive value of this approach. The potential use of a multimarker approach to increase the diagnostic and prognostic value of these clinical assessments is also discussed.
22337955 Meta-analysis confirms a role for deletion in FCGR3B in autoimmune phenotypes. 2012 May 15 Although deletion in the low-affinity IgG receptor gene FCGR3B has repeatedly been implicated in systemic autoimmune disease, the role of FCGR3B copy number variation (CNV) in autoimmunity still remains unclear. Factors such as study size, ethnicity, specific disease phenotype and experimental methodology may explain these conflicting results. Here we aimed at using meta-analysis to assess the role for FCGR3B CNV in autoimmunity. We excluded studies using SybrGreen-based genotyping and found strong evidence for association between low (<2) FCGR3B CN and systemic lupus erythematosus [OR = 1.59 (1.32-1.92), P(meta)=9.1 × 10(-7)], but not for rheumatoid arthritis [OR = 1.36 (0.89-2.06), P= 0.15]. However, a combined autoimmune phenotype analysis supports the deletion of FCGR3B as a risk factor for non-organ-specific autoimmunity [OR = 1.44 (1.28-1.62), P(meta)= 2.9 × 10(-9)]. This meta-analysis implicates the clearance of immune complex in the etiology of non-organ-specific autoimmune disease.
22312480 CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to A 2012 CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.
22311407 Development of clinical practice guidelines in 11 common diseases with Chinese medicine in 2012 Feb OBJECTIVE: To analyze the clinical practice guideline (CPG) development on 11 common diseases with Chinese medicine (CM) interventions in China. METHODS: The CPGs of 11 common diseases which could be treated effectively with CM had been published between 1980 and 2010 in China. The 11 diseases include coronary heart disease (angina pectoris), hypertension, chronic gastritis, rheumatoid arthritis, cerebral infarction, migraine, diabetes, primary osteoporosis, insomnia, common cold, and IgA nephropathy. The issuing organization, date of publication, development methods, and citation rate of the CPGs were analyzed. According to the development method, each guideline was categorized as consensus-based (CB), evidence-based (EB), or consensus based with no explicit consideration of evidence-based (CB-EB). RESULTS: Thirty-three CPGs on the 11 common diseases were found: 20 guidelines were classified as CB, 13 as CB-EB and none as EB. Fifteen CPGs were issued by the China Association of Chinese Medicine, 8 by professional working groups, and 4 by the State Administration of Traditional Chinese Medicine. Six guidelines were published between 1980 and 1990, 9 between 1991 and 2000, and 18 between 2001 and 2010. Fifty-eight percent of these guidelines have not been amended timely. Only 54.5% (18/33) of the 33 guidelines were cited by other researchers and 45.5% (15/33) percent had never been cited. CONCLUSIONS: Most CPGs developed for 11 common diseases with CM approaches in China are consensus, and their citation rates are relatively low. The results suggest that more EB CPG or CPG strictly based on expert consensus could be developed, and great efforts should be made for future CM CPG application.
22266050 Development and characterization of a novel drug nanocarrier for oral delivery, based on s 2012 Jun 10 β-casein is an amphiphilic protein that self-organizes into well-defined core-shell micelles. We developed these micelles as efficient nanocarriers for oral drug delivery. Our model drug is celecoxib, an anti-inflammatory hydrophobic drug utilized for treatment of rheumatoid arthritis and osteoarthritis, now also evaluated as a potent anticancer drug. This system is unique as it enables encapsulation loads >100-fold higher than other β-casein/drug formulations, and does not require additives as do other formulations that have high loadings. This is combined with the ability to lyophilize the formulation without a cryoprotectant, long-term physical and chemical stability of the resulting powder, and fully reversible reconstitution of the structures by rehydration. The dry dosage form, in which >95% of the drug is encapsulated, meets the daily dose. Cryo-TEM and DLS prove that drug encapsulation results in micelle swelling, and X-ray diffraction shows that the encapsulated drug is amorphous. Altogether, our novel dosage form is highly advantageous for oral administration.
22228035 3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen-acti 2012 May The p38α mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and psoriasis. Herein, we have performed 3D-QSAR and molecular docking analysis on a novel series of biphenyl amides to design potent p38 MAP kinase inhibitors. This study correlates the p38 MAP kinase inhibitory activities of 80 biphenyl amide derivatives to several stereochemical parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The resulting model from CoMFA and CoMSIA exhibited excellent [Formula: see text] values of 0.979 and 0.942, and [Formula: see text] values of 0.766 and 0.748, respectively. CoMFA predicted [Formula: see text] of 0.987 and CoMSIA predicted [Formula: see text] of 0.761 showed that the predicted values were in good agreement with experimental values. Glide (5.5) program gave the path for binding mode exploration between the inhibitors and p38α MAP kinase. We have accordingly designed novel p38α MAP kinase inhibitors by utilizing LeapFrog and predicted with excellent activity in the developed models.
22094569 Preoperative nutritional status and post-operative infection in total knee replacements: a 2011 Sep PURPOSE: To assess the potential relationship between preoperative nutritional status, including anthropometric parameters, and infection following total knee replacement surgery. METHODS: A total of 213 patients undergoing total knee replacement between December 2007 and May 2008 were prospectively studied. Patients with rheumatoid arthritis were excluded. For each patient we pre-operatively checked biochemical and anthropometric parameters of nutrition information about co-morbidities such as diabetes and high blood pressure, ASA score, age, and gender. Information about early infections, both superficial and deep, was collected. A descriptive statistical analysis and univariate/multivariate logistic regression model for risk factors were performed. RESULTS: Eleven patients (5.16%) had an infection, 5 deep and 6 superficial. Neither co-morbidities nor preoperatively biochemical parameters were associated with infection. However, in the univariate logistic regression model there was an inversely proportional relationship between triceps skinfold (TSF) and infection. After adjusting for age, ASA score and gender (multivariate logistic regression), TSF remained significantly associated with infection. CONCLUSION: There was a statistically significant association between TSF and post-operative infection risk after TKR. LEVEL OF EVIDENCE: Level I (Prospective prognostic study).
22021748 Poor physical function, pain and limited exercise: risk factors for premature mortality in 2011 Jun 18 OBJECTIVE: To analyse poor physical function, pain, limited exercise and smoking, assessed in a patient-friendly self-report questionnaire format that has been completed by every patient at every visit over 20-30 years in the authors' and other usual care settings, to predict 5-year mortality in a general older population. METHODS: An extended version of a Multidimensional Health Assessment Questionnaire was mailed to 2000 subjects in Finland, identified as a randomly selected control cohort for a rheumatoid arthritis cohort. The questionnaire included queries concerning baseline physical function, pain, exercise and smoking status, identical to the clinic version, as well as age and 25 medical conditions. Five-year survival was analysed according to descriptive statistics, Kaplan-Meier curves and Cox regressions. RESULTS: The questionnaire was returned by 1523 subjects (76%). Five-year survival was 94% in all subjects, 98% in subjects with no disease or no acutely life-threatening disease, and 17% in subjects with an acutely life-threatening disease. Hazard ratios (HRs) for 5-year mortality were 3.5 for poor physical function, 2.2 for pain, 5.2 for limited exercise and 4.6 for smoking (p<0.01); 5-year survivals were 93%, 97%, 93% and 95%, respectively, compared with 91% for hypertension. Each of the four patient history variables predicted mortality at higher levels in subjects who reported no versus one or more acutely life-threatening conditions. CONCLUSIONS: Poor physical function, pain, limited exercise and smoking can be assessed systematically on a simple standard Multidimensional Health Assessment Questionnaire, to identify potentially modifiable risk factors for premature mortality in the infrastructure of usual medical care and health maintenance.
21918268 Rituximab. 2011 Aug Rituximab is a chimeric mouse-human monoclonal antibody against the CD 20 antigen on the surface of B lymphocytes. It binds to CD20 and causes B cell death by antibody dependant cell-mediated cytotoxicity, complement mediated cytotoxicity and apoptosis. It leads to rapid and sustained depletion of B cells. It is licensed for use in adults with CD20 positive B-cell lymphoma and rheumatoid arthritis. In children, it has been used in a variety of off-label indications with promising results. It has proved useful as salvage therapy in relapsed refractory non-Hodgkins lymphoma and leukemia, and in hematological conditions including chronic immune thrombocytopenic purpura, hemophilia with inhibitors, and autoimmune hemolytic anemia. It has also proved effective in autoimmune conditions like primary systemic vasculitis and systemic lupus erythematosis. Nephrotic syndrome and opsoclonus-myoclonus syndrome are among the emerging indications for rituximab. In solid organ transplantation, rituximab is useful in the prevention and treatment of acute and chronic rejection as well as in post transplantation lymphoproliferative disease. Toxicity includes acute infusion reactions, susceptibility to bacterial infections, and reactivation of viral infections.
21798302 Epidemiologic studies of glyphosate and non-cancer health outcomes: a review. 2011 Nov The United States (US) Environmental Protection Agency (EPA) and other regulatory agencies around the world have registered glyphosate as a broad-spectrum herbicide for use on multiple food and non-food use crops. To examine potential health risks in humans, we searched and reviewed the literature to evaluate whether exposure to glyphosate is associated causally with non-cancer health risks in humans. We also reviewed biomonitoring studies of glyphosate to allow for a more comprehensive discussion of issues related to exposure assessment and misclassification. Cohort, case-control and cross-sectional studies on glyphosate and non-cancer outcomes evaluated a variety of endpoints, including non-cancer respiratory conditions, diabetes, myocardial infarction, reproductive and developmental outcomes, rheumatoid arthritis, thyroid disease, and Parkinson's disease. Our review found no evidence of a consistent pattern of positive associations indicating a causal relationship between any disease and exposure to glyphosate. Most reported associations were weak and not significantly different from 1.0. Because accurate exposure measurement is crucial for valid results, it is recommended that pesticide-specific exposure algorithms be developed and validated.
23427598 [Effect of Bushen Qianggu decoction on the proliferation of synovial fibroblasts and expre 2012 Nov OBJECTIVE: To observe the effects of Bushen Qianggu decoction proliferation and PCNA and Bcl-2 expression. METHODS: Serum containing BQD was made and synovial fibroblasts were separated and cultured and passaged in vitro. Four groups were divided as 20% blank control group, serum containing 20% Tripterygium wilfordii multi-glycosides drug (TWMD), 20% of serum containing high and low of BQD, respectively. Serum containing drugs of different concentration were added into the synovial fibroblasts of the third generation, and then the synovial fibroblasts were cultured continued. The effects of different drugs on synovial fibroblasts and PCNA and Bcl-2 expression were observed. RESULTS: Compared with the control serum, BQD-containing serum promoted the apoptosis of synovial fibroblasts (P < 0.000 1); especially, high dose could inhibit proliferation. The expression of PCNA and Bcl-2 was significantly lower in BQD-containing serum (P < 0.000 1 vs control group). CONCLUSION: BQD can promote the apoptosis of synovial fibroblasts by improving of expression of PCNA and Bcl-2, which may be one of the mechanisms of BQD in preventing and treating osteoporosis of rheumatoid arthritis.
23305364 Suppression of TLR signaling by targeting TIR domain-containing proteins. 2012 Dec Toll-like receptors (TLRs) recognize molecules specific to pathogens and endogenous danger signals. Binding of agonists to the ectodomain of the receptor initiates TLR activation and is followed by the association of receptor cytosolic Toll/Interleukin-1 receptor (TIR) domains with TIR domains of adapter proteins leading to the assembly of signaling cascade of protein kinases that ultimately trigger the activation of transcription factors and expression of genes involved in the immune response. Excessive activation of TIR-domain mediated signaling has been implicated in inflammatory diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, colitis) as well as in the development of cancer. Targeting receptor-adapter interactions represents a potential strategy for the therapeutic TLR/IL-1R-specific inhibition due to the unique interacting domains involved. Peptide and protein-domain binding TLR inhibitors originating from the interacting surfaces of TIR-domain containing proteins can bind to the site on their target interacting protein thereby preventing the assembly of the functional signaling complex. Here we review protein-domain, peptide and peptidomimetic inhibitors targeting TIR-domain mediated interactions and their application demonstrated on in vitro and in vivo models. Recent structural data and elucidation of the molecular mechanisms of TIR-domain mediated signaling enabled the development of peptide inhibitors from TIR domains of TLRs and adapters, MyD88 intermediary domain as well as improved protein inhibitors based on TIR domain dimerization, mimicking bacterial TIR-domain containing immunosuppressors (TCPs) which we discuss with challenges concerning the delivery and specificity of inhibitors targeting TLR adapters.
23253448 P2X receptors as drug targets. 2013 Apr The study of P2X receptors has long been handicapped by a poverty of small-molecule tools that serve as selective agonists and antagonists. There has been progress, particularly in the past 10 years, as cell-based high-throughput screening methods were applied, together with large chemical libraries. This has delivered some drug-like molecules in several chemical classes that selectively target P2X1, P2X3, or P2X7 receptors. Some of these are, or have been, in clinical trials for rheumatoid arthritis, pain, and cough. Current preclinical research programs are studying P2X receptor involvement in pain, inflammation, osteoporosis, multiple sclerosis, spinal cord injury, and bladder dysfunction. The determination of the atomic structure of P2X receptors in closed and open (ATP-bound) states by X-ray crystallography is now allowing new approaches by molecular modeling. This is supported by a large body of previous work using mutagenesis and functional expression, and is now being supplemented by molecular dynamic simulations and in silico ligand docking. These approaches should lead to P2X receptors soon taking their place alongside other ion channel proteins as therapeutically important drug targets.
23209344 The role of Src kinase in macrophage-mediated inflammatory responses. 2012 Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.
23201917 Cartilage as a target of autoimmunity: a thin layer. 2013 Mar The articular cartilage is an important component of human organism that has elasticity, low-friction surface, and ability to withstand great physical forces. The structure consists of collagens and proteoglycans, whereas non-collagenous proteins are needed for the organization and modulation of the molecular networks. The structural elements of the cartilage are typical to that tissue and could, in part, account for the localization of the inflammatory response to the joint. For this reason cartilage is of particular interest in autoimmunity as it may represent a source of antigens. It is well known that sensitization with collagens can produce autoimmune rheumatic diseases in experimental models. So far, the cartilage proteins that have been clearly characterized to be arthritogenic in experimental models involve types II and XI collagen, cartilage oligomeric matrix protein, and aggrecan. It is likely that these proteins are also recognized at different stages in the development of rheumatoid arthritis and in other autoimmune diseases. The mechanisms determining the trigger of a cartilage-specific immune response, its development and outcome are poorly understood. Most likely, the distribution and concentration of a specific cartilage protein may play a role by eliciting an autoimmune response. Indeed, the inflammatory processes lead to tissue damage mediated by the intervention of several factors such as autoantibodies, cytokines as well as cells of the innate an adaptive immunity. For this reason, even previously-considered degenerative diseases, such as osteoarthritis, should now be re-evaluated as at least partly inflammatory-driven. Thus, the objective of this review is to describe the clinical conditions sustained by the immune-mediated reactions to cartilage, which represents the target organ in a number of autoimmune diseases.
23177218 Aurin tricarboxylic acid self-protects by inhibiting aberrant complement activation at the 2013 May Aberrant complement activation is known to exacerbate the pathology in a spectrum of degenerative diseases of aging. We previously reported that aurin tricarboxylic acid (ATA) is an orally effective agent which prevents formation of the membrane attack complex of complement. It inhibits C9 attachment to tissue bound C5b678 and thus prevents bystander lysis of host cells. In this study, we investigated the effects of ATA on the alternative complement pathway. We found that ATA prevented cleavage of the tissue bound properdin-C3b-Factor B complex into the active C3 convertase enzyme properdin-C3b-Factor Bb. This inhibition was reversed by adding Factor D to the serum. Using enzyme-linked immunosorbent type assays, we established that ATA binds directly to Factor D and C9 but not to properdin or other complement proteins. We conclude that ATA, by inhibiting at two stages of the alternative pathway, might be a particularly effective therapeutic agent in conditions such as macular degeneration, paroxysmal nocturnal hemoglobinemia, and rheumatoid arthritis, in which activation of the alternative complement pathway initiates self damage.
23142594 RANKL downregulates cell surface CXCR6 expression through JAK2/STAT3 signaling pathway dur 2012 Dec 14 The receptor activator of nuclear factor-κB ligand (RANKL), as a member of the tumor necrosis factor (TNF) family, plays an essential role in osteoclast differentiation and function. Chemokines and their receptors have recently been shown to play critical roles in osteoclastogenesis, however, whether CXCL16-CXCR6 plays role in RANKL-mediated osteoclastogenesis is unknown. In this study, we first reported that RANKL decreased CXCR6 in a dose-dependent manner, which may be through deactivation of Akt and STAT3 signaling induced by CXCL16. Interestingly, RANKL-mediated CXCR6 reduction may be associated to the activation of STAT3 by phosphorylation. When STAT3 activation was blocked by JAK2/STAT3 inhibitor AG490, RANKL failed to shut down CXCR6 expression during osteoclastogenesis. However, CXCL16 alone did not augment RANKL-mediated osteoclast differentiation and did not alter RANKL-receptor RANK mRNA expression. These results demonstrate that reduction of CXCL16-CXCR6 is critical in RANKL-mediated osteoclastogenesis, which is mainly through the activation of JAK2/STAT3 signaling. CXCL16-CXCR6 axis may become a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis and osteoporosis.