Rheumatoid Arthritis: Zhang L

Zhang L, Hu JJ, Lin JW, Fang WS, Du GH. · Institute of Materia Medica, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, PR China. · J Ethnopharmacol. · Pubmed #19443147 No free full text.

Abstract: AIM OF THE STUDY: This study evaluates the anti-inflammatory and analgesic activities of the ethanol and aqueous extracts of a Tibetan herb Pterocephalus hookeri (C.B. Clarke) Höeck to provide experimental evidence for its traditional use such as cold, flu and rheumatoid arthritis. MATERIALS AND METHODS: Investigations on the analgesic effects of P. hookeri (C.B. Clarke) Höeck were carried out, including hot-plate test and acetic acid-induced writhing. The anti-inflammatory activities were observed by utilizing the following models: carrageenin-induced edema of the hind paw of rats, cotton pellet-induced granuloma formation in rats, acetic acid-induced permeability, and xylene-induced ear edema in mice. The effects of the administration of indomethacin were also studied. RESULTS: It has been shown that the ethanol and aqueous extracts significantly increased the hot-plate pain threshold and reduced acetic acid-induced writhing response in mice. The ethanol and aqueous extracts remarkably inhibited the increase in vascular permeability induced by acetic acid and ear edema induced by xylene. The ethanol extract also significantly decreased the carrageenin-induced rat paw edema perimeter and inhibited the increase of granuloma weight. CONCLUSION: The results show that the ethanol and aqueous extracts have both central and peripheral analgesic activities and as anti-inflammatory effects, supporting the traditional application of this herb in treating various diseases associated with inflammation and pain.

Wang P, Yang L, You X, Singh GK, Zhang L, Yan Y, Sung KL. · College of Bioengineering, Chongqing University, Chongqing, China. · Connect Tissue Res. · Pubmed #19296301 No free full text.

Abstract: Mechanical stretch plays a crucial role in articular joints. In rheumatoid arthritis (RA), it is well known that fibroblast-like synoviocytes (FLS) produce matrix metalloproteinases (MMPs), resulting in local invasion into and degradation of bone and cartilage. We sought to examine whether mechanical stretch regulates the expression and underlying signal pathways of MMP secretion (MMP-1, -3, -13) in RA-FLS. FLS were grown on elastic silicone membrane in an equibiaxial strain apparatus and were exposed to 6% mechanical stretch (equivalent to gentle stretch exercise) for 15 min and 75 min, respectively. Semiquantitative PCR and real-time PCR were used to measure and analyze gene expression. Protein levels were determined by Western blotting. The results showed that 15 min of mechanical stretch inhibited MMP-1 and MMP-13 mRNA and protein level. However, the degree of inhibition by 75 min of stretch in expression of MMP-1 and MMP-13 was lower compared with 15 min stretch groups. The mRNA expression of ERK-1, ets-1 and citied-2 were increased by 6% mechanical stretch under both time points, however c-jun and c-fos mRNA level were affected differently after 15 min and 75 min mechanical stretch compared to control group. There were no significant changes on MMP-3 and ets-2 mRNA level under both 6% mechanical stretch time points. In the presence of pro-inflammatory cytokines (IL-1beta and TNF-alpha), the stretch also reduced the mRNA expression of MMP-1 and MMP-13. In short, our results showed that gentle mechanical strain affects MMP-1 and MMP-13 expression, potentially through the ERK-1-ets-1-cited-2-c-jun signaling pathway.

Huang W, Wang P, Liu Z, Zhang L. · Department of Computer Science, Virginia Tech, 2050 Torgerson Hall, Blacksburg, VA 24061-0106, USA. · BMC Bioinformatics. · Pubmed #19208172 links to  free full text

Abstract: BACKGROUND: Genome-wide association studies prove to be a powerful approach to identify the genetic basis of different human diseases. We studied the relationship between seven diseases characterized in a previous genome-wide association study by the Wellcome Trust Case Control Consortium. Instead of doing a horizontal association of SNPs to diseases, we did a vertical analysis of disease associations by comparing the genetic similarities of diseases. Our analysis was carried out at four levels - the nucleotide level (SNPs), the gene level, the protein level (through protein-protein interaction network), and the phenotype level. RESULTS: Our results show that Crohn's disease, rheumatoid arthritis, and type 1 diabetes share evidence of genetic associations at all levels of analysis, offering strong molecular support for the current grouping of the diseases. On the other hand, coronary artery disease, hypertension, and type 2 diabetes, despite being considered as a natural group with potential aetiological overlap, do not show any evidence of shared genetic basis at all levels. CONCLUSION: Our study is a first attempt on mining of GWA data to examine genetic associations between different diseases. The positive result is apparently not a coincidence and hence demonstrates the promising use of our approach.

Studelska DR, Mandik-Nayak L, Zhou X, Pan J, Weiser P, McDowell LM, Lu H, Liapis H, Allen PM, Shih FF, Zhang L. · Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. · J Biol Chem. · Pubmed #18948258 No free full text.

Abstract: In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However, how GPI localizes to the joint remains unclear. We show that glycosaminoglycans (GAGs) are the high affinity (83 nm) joint receptors for GPI. The binding affinity and structural differences between mouse paw/ankle GAGs and elbows/knee GAGs correlated with the distal to proximal disease severity in these joints. We found that cartilage surface GPI binding was greatly reduced by either chondroitinase ABC or beta-glucuronidase treatment. We also identified several inhibitors that inhibit both GPI/GAG interaction and GPI enzymatic activities, which suggests that the GPI GAG-binding domain overlaps with the active site of GPI enzyme. Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses.

Baek HJ, Zhang L, Jarvis LB, Gaston JS. · Department of Medicine, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK. · Rheumatology (Oxford). · Pubmed #18390584 No free full text.

Abstract: OBJECTIVE: To measure the frequencies of IL-4+ CD8+ T cells from patients with AS and RA, and to assess their clinical relevance and properties. METHODS: Peripheral blood (PB) and clinical data were obtained from 37 AS, 36 RA patients and 37 healthy controls. We also generated IL-4-producing CD8+ T cell lines and clones by co-culture with autologous dendritic cells. Using flow cytometry, we evaluated intracellular cytokine expression by T cells following stimulation with PMA and calcium ionophore. The phenotype and ability of the IL-4-producing CD8+ T cell clones to suppress IFN-gamma production were examined. RESULTS: The percentages of IL-4+ CD8+ T cells were higher in PB of patients with AS and RA than controls (medians 0.90 and 0.84% vs 0.30%). In RA, patients with active inflammation had an increased percentage of IL-4+ CD8+ T cells. Higher frequencies of IL-4+ CD8+ T cells were also found in CD8+ T cell lines established from patients with arthritis. Interestingly, most IL-4+ CD8+ T cells produced TNF-alpha. Cloning the CD8+ T cell lines yielded more IL-4-producing clones from AS (23%) and RA patients (14%) than from controls (7%). The ability to suppress IFN-gamma production was observed in 56% (AS) and 85% (RA) of IL-4-producing clones. Suppressive IL-4+ CD8+ T cell clones from RA patients showed a similar regulatory phenotype to the clones previously isolated from AS patients. CONCLUSIONS: Expansion of IL-4+ CD8+ T cells, which may include precursors of a regulatory CD8+ T cell subset, may represent a general response to chronic joint inflammation.

Li R, Li J, Cai L, Hu CM, Zhang L. · School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, China. · J Pharm Pharmacol. · Pubmed #18237470 No free full text.

Abstract: The citrus flavonoid hesperidin has been reported to possess a wide range of pharmacological properties. We have investigated the preventive and therapeutic effects of hesperidin on the development of adjuvant arthritis (AA), a rat model of rheumatoid arthritis (RA). Freund's complete adjuvant was used to induce AA in rats. Secondary paw swelling, polyarthritis index and histopathological assessment of ankle joints were used to evaluate the effects of hesperidin on AA rats. Concanavalin-A-induced T-lymphocyte proliferation and interleukin (IL)-2 production by splenocytes were measured using the MTT assay. Levels of IL-1, IL-6 and tumour necrosis factor (TNF)-alpha secreted by peritoneal macrophages (PM) were measured by RIA. Intragastric administration of hesperidin significantly attenuated secondary paw swelling and reduced the polyarthritis index of AA rats in a dose-dependent manner. In addition, hesperidin clearly ameliorated the pathological changes in AA rats. Hesperidin also restored the suppression of T-lymphocyte proliferation and IL-2 production, and downregulated production of IL-1, IL-6 and TNF-alpha by PM in AA rats. Our results suggest that hesperidin improves AA by downregulating the function of over-active macrophages and by up-regulating the activities of dysfunctional T lymphocytes. Hesperidin may therefore have therapeutic value for the clinical treatment of RA. Further research is required to clarify the detailed mechanisms of the protective effects of hesperidin on AA.

Tam LS, Leung PC, Li TK, Zhang L, Li EK. · The Department of Medicine & Therapeutics, The Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. · BMC Complement Altern Med. · Pubmed #17980044 links to  free full text

Abstract: BACKGROUND: In planning a randomized controlled trial of acupuncture, we conducted a pilot study using validated outcome measures to assess the feasibility of the protocol, and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis (RA). METHODS: The study employs a randomized, prospective, double-blind, placebo-controlled trial to evaluate the effect of electroacupuncture (EA), traditional Chinese acupuncture (TCA) and sham acupuncture (Sham) in patients with RA. All patients received 20 sessions over a period of 10 weeks. Six acupuncture points were chosen. Primary outcome is the changes in the pain score. Secondary outcomes included the changes in the ACR core disease measures, DAS 28 score and the number of patients who achieved ACR 20 at week 10. RESULTS: From 80 eligible patients, 36 patients with mean age of 58 +/- 10 years and disease duration of 9.3 +/- 6.4 years were recruited. Twelve patients were randomized to each group. Twelve, 10 and 7 patients from the EA, TCA and Sham group respectively completed the study at 20 weeks (p < 0.03); all except one of the premature dropouts were due to lack of efficacy. At week 10, the pain score remained unchanged in all 3 groups. The number of tender joints was significantly reduced for the EA and TCA groups. Physician's global score was significantly reduced for the EA group and patient's global score was significantly reduced for the TCA group. All the outcomes except patient's global score remained unchanged in the Sham group. CONCLUSION: This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00404443.

Zhang L, Visscher D, Rihal C, Aubry MC. · Department of Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Rheumatol Int. · Pubmed #17520258 No free full text.

Abstract: Mixed connective tissue disease (MCTD) is a systemic disease seen in a group of patients with overlapping clinical features of lupus, scleroderma, polymyositis, and rheumatoid arthritis. A defining feature of MCTD is the presence of antibodies against the U1-ribonucleoprotein (U1-RNP) complex. Pulmonary hypertension is the major cause of death in MCTD. We report an autopsy case of MCTD with pulmonary hypertension. The U1-RNP antibody of this patient was 171.9 U (normal < 25.0 U). The immediate cause of death was attributed to acute pulmonary embolism at left lower lobe. A severe vasculopathy characterized by fibrotic occlusion of small veins and venules, associated with prominent capillary congestion, was consistent with pulmonary veno-occlusive disease (PVOD). This is the first case reported in which PVOD is the primary cause of pulmonary hypertension in MCTD.

Wang J, Li C, Liu Y, Mei W, Yu S, Liu C, Zhang L, Cao X, Kimberly RP, Grizzle W, Zhang HG. · Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294-0007, USA. · Am J Pathol. · Pubmed #16936264 links to  free full text

Abstract: Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-alpha stimulation. Here, we show that JAB1 is a critical regulator of the TNF-alpha-mediated anti-apo-ptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF-alpha-induced apoptosis response, reduction of nuclear factor-kappaB activity, delayed degradation of IkappaB-alpha, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the anti-apoptotic signal on binding of TNF-alpha to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF-alpha stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF-alpha can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-kappaB and JNK in RA FLSs.

Zhang HG, Liu C, Su K, Su K, Yu S, Zhang L, Zhang S, Wang J, Cao X, Grizzle W, Kimberly RP. · Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, 35294, USA. · J Immunol. · Pubmed #16751383 links to  free full text

Abstract: In common with many other cell types, synovial fibroblasts produce exosomes. In this study, we show that the exosomes produced by synovial fibroblasts obtained from individuals with rheumatoid arthritis (RASF), but not exosomes produced by synovial fibroblasts obtained from individuals with osteoarthritis, contain a membrane bound form of TNF-alpha as demonstrated by colloidal gold immunostaining of TNF-alpha and confirmed by both Western blot and mass spectrometry. The RASF-derived exosomes, but not exosomes derived from fibroblasts obtained from individuals with osteoarthritis, are cytotoxic for the L929 cell, a TNF-alpha-sensitive cell line, and stimulate activation of NF-kappaB and induction of collagenase-1 in RASF. These effects are blocked by addition of soluble TNFR1 (sTNFbp), suggesting that a TNF-alpha-signaling pathway mediates these biological activities. sTNFbp also reduced the production of exosomes by RASF, suggesting the interruption of a positive amplification loop. Exosomes can transmit signals between cells, and RASF exosomes, effectively taken up by anti-CD3-activated T cells, activated AKT and NF-kappaB and rendered these activated T cells resistant to apoptosis. Neutralization of exosomal membrane TNF-alpha by sTNFbp partially reversed this resistance, suggesting that not only TNF-alpha but also additional exosomal proteins may contribute to the development of apoptosis resistance.

Liu W, Zhang L, Xu Z. · Rheumatic Department, the First Hospital Affiliated to Tianjin College of TCM, Tianjin 300193. · Zhongguo Zhong Xi Yi Jie He Za Zhi. · Pubmed #16548360 No free full text.

Abstract: OBJECTIVE: To study the indication and clinical efficacy of Biqi capsule (BC) in treating patients with rheumatoid arthritis (RA). METHODS: One hundred and forty-two RA patients were randomly divided into the BC treated group and the control group treated with nimesulide tablet (NT). There were 36 patients with dampness-heat blockage syndrome type and 35 patients with Qi deficiency and blood stasis syndrome type in each group. The treatment course lasted for 8 weeks. RESULTS: The total effective rate in the BC group was 66.2% (47 cases), while that in the control group was 60.6% (43 cases). The total effective rate in the patients with Qi deficiency and blood stasis syndrome type in the BC group was 91.4%, superior to that with dampness-heat blockage type (41.7%). Only one patient showed mild adverse reaction in the BC group. CONCLUSION: BC is a kind of safe and effective herble medicine for treatment of RA, especially for those of Qi deficiency and blood stasis syndrome type.

Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. · Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · J Immunol. · Pubmed #16339568 links to  free full text

Abstract: Macrophages are activated during an inflammatory response and produce multiple inflammatory cytokines. IL-18 is one of the most important innate cytokines produced from macrophages in the early stages of the inflammatory immune response. Monocyte chemoattractant protein (MCP-1) is expressed in many inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, and its expression is correlated with the severity of the disease. Both IL-18 and MCP-1 have been shown to be involved in inflammatory immune responses. However, it has been unclear whether IL-18 is involved in the induction of MCP-1. This investigation was initiated to determine whether IL-18 can induce MCP-1 production, and if so, by which signal transduction pathways. We found that IL-18 induced the production of MCP-1 in macrophages, which was IL-12-independent and was not mediated by autocrine cytokines such as IFN-gamma or TNF-alpha. We then examined signal transduction pathways involved in IL-18-induced MCP-1 production. We found that IL-18 did not activate the IkappaB kinase/NF-kappaB pathway, evidenced by no degradation of IkappaBalpha and no translocation of NF-kappaB p65 to the nucleus in IL-18-stimulated macrophages. Instead, IL-18 activated the PI3K/Akt and MEK/ERK1/2 pathways. Inhibition of either of these pathways attenuated MCP-1 production in macrophages, and inhibition of both signaling pathways resulted in the complete inhibition of MCP-1 production. On the basis of these observations, we conclude that IL-18 induces MCP-1 production through the PI3K/Akt and MEK/ERK1/2 pathways in macrophages.

Zhao W, Zhang L, Kobari Y, Misaki Y, Yamamoto K. · Department of Immunology, Capital University of Medical Sciences, Beijing, China. · Cell Mol Immunol. · Pubmed #16225773 links to  free full text

Abstract: SKG mouse, as a model of spontaneous rheumatoid arthritis (RA) bred recent years, is similar to the patients with RA. We analyzed the clonotypes of T cell infiltrating into joints of SKG mice in initial stage and late stage of RA by using reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP). The results indicated that the percentages of clonotypes TCR Vbeta2 and Vbeta8.2 of T cell clonotypes increased obviously to 72.3% and 60.2%, respectively. Mice number with identical TCR Vbeta2 and Vbeta8.2 clonotypes also clearly increased in late stage of disease to 100% and 75%, respectively. These results mean that T cells with TCR Vbeta2 and Vbeta8.2 clonotypes probably play an important role in RA progression of SKG mouse. Sequencing of the extracted DNA verified that common bands on SSCP gel were derived from the same T cell clones among samples from different joints. The results we obtained implied that RT-PCR/SSCP method was a sensitive and credible method for analyzing T cell clonotypes. When the T cells of SKG mouse were adoptively transferred to a nude mouse, it was verified that the T cells infiltrating into joints were related to morbid formation of RA.

Wu X, Zhang L, Qu Y, Li MY, Jiang ZH, Li H. · Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, China. · Sichuan Da Xue Xue Bao Yi Xue Ban. · Pubmed #16078559 No free full text.

Abstract: OBJECTIVE: To construct the interleukin-18-PE38 fusion gene expression vector and explore the expression of the fusion gene in the chondrocyte. METHODS: The recombinant eukaryotic expression vector PsecTag2B-IL-18-PE38 was constructed by inserting interleukin-18-PE38 fusion gene into eukaryotic expression vector PsecTag2B with molecular cloning technique. It was confirmed by restrictive enzymes (EcoR I) digestion assay and PCR. The vector was transfected into primary chrondrocyte by liposome protocol, and the transient expression was identified by fluorescence immunocytochemical assay. RESULTS: Restrictive enzymes digestion analysis and PCR revealed that the interleukin-18-PE38 fusion gene was cloned into the eukaryotic expression vector PsecTag2B successfully. Immunofluorescence photograph of fluorescence immunocytochemical method confirmed that the fusion gene can be expressed in the cytomembrane and cytoplasm. CONCLUSION: The results confirmed that PsecTag2B-IL-18-PE38 fusion gene can be expressed in the chondrocyte, which could serve as a foundation for the study on rheumatoid arthritis therapy.

Wu X, Yang C, Zhang L. · Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu Sichuan, 610041, PR China. · Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. · Pubmed #15921325 No free full text.

Abstract: OBJECTIVE: To establish a kind of gene therapy method of rheumatoid arthritis, to construct the interleukin-18-PE38 fusion gene expression vector and to explore the expression of the fusion gene in the chondrocytes and 3T3 cells. METHODS: Interleukin-18-PE38 fusion gene was cleaved from plasmid PRKL459k-IL-18-PE38 by restriction enzyme digestion, then linked with vectors PsecTag2B and transformed into competence bacteria, positive clones were selected and confirmed by restrictive enzyme (EcoRI) digestion assay. The rearrangement plasmid PsecTag2B-IL-18-PE38 was transfected into 3T3 cells and mouse chondrocytes by liposome protocol (experimental group), null vector was used as negative control, and the transient expression was identified by fluorescence Restrictive enzymes digestion analysis revealed that the length of the interleukin-immunocytochemical assay. RESULTS: 18-PE38 fusion gene was 6000 bp. Fluorescence immunocytochemical method showed that fluorescence intensity of the experimental group is strong,while fluorescence intensity of the control group is weak. CONCLUSION: The eukaryotic expression vector PsecTag2B-IL-18-PE38 is established successfully which can be expressed in the 3T3 cells and mouse chondrocytes. Our results lay a foundation for the further investigation for rheumatoid arthritis therapy.

Amano T, Yamasaki S, Yagishita N, Tsuchimochi K, Shin H, Kawahara K, Aratani S, Fujita H, Zhang L, Ikeda R, Fujii R, Miura N, Komiya S, Nishioka K, Maruyama I, Fukamizu A, Nakajima T. · Department of Genome Science, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8512, Japan. · Genes Dev. · Pubmed #12975321 links to  free full text

Abstract: Rheumatoid arthritis (RA) is one of the most critical articular diseases with synovial hyperplasia followed by impairment of quality of life. However, the mechanism(s) that regulates synovial cell outgrowth is not fully understood. To clarify its mechanism(s), we carried out immunoscreening by using antirheumatoid synovial cell antibody and identified and cloned "Synoviolin/Hrd1", an E3 ubiquitin ligase. Synoviolin/Hrd1 was highly expressed in the rheumatoid synovium, and mice overexpressing this enzyme developed spontaneous arthropathy. Conversely, synoviolin/hrd1(+/-) mice were resistant to collagen-induced arthritis by enhanced apoptosis of synovial cells. We conclude that Synoviolin/Hrd1 is a novel causative factor for arthropathy by triggering synovial cell outgrowth through its antiapoptotic effects. Our findings provide a new pathogenetic model of RA and suggest that Synoviolin/Hrd1 could be targeted as a therapeutic strategy for RA.

Wang R, Zhang L, Zhang X, Moreno J, Celluzzi C, Tondravi M, Shi Y. · Department of Immunology, Jerome H. Holland Laboratory, American Red Cross, Rockville, USA. · Eur J Immunol. · Pubmed #11920576 No free full text.

Abstract: Receptor activator of NF-kappaB ligand (RANKL) is a type II membrane protein of the TNF family and plays a critical role in the regulation of osteoclastogenesis. RANKL expressed on osteoblastic stromal cells has been shown to support osteoclast differentiation originated from hematopoietic precursors. Interestingly, RANKL is also expressed on cells of the immune system including T cells and dendritic cells. We have shown that anti-CD3 could induce RANKL expression in T cell hybridoma A1.1 cells and splenic T cells. RANKL expressed on T cells could effectively induce osteoclast formation from the whole population of murine splenocytes. Furthermore, we have found that the induction of RANKL expression is solely dependent on TCR activation-induced Ca2+ mobilization since its expression can be blocked by cyclosporine A and TMB-8, a Ca2+ mobilization inhibitor. Additionally, treatment of A1.1 cells with ionomycin alone also strongly induces RANKL expression, while phorbol myristate acetate by itself does not. Moreover, although inhibition of c-myc has significant effects on anti-CD3-induced Fas ligand (FasL) expression, we have found that the anti-CD3-induced RANKL expression is independent of c-myc. Surprisingly, in contrast to its inhibitory effect on FasL expression, TGF-beta dramatically increased the expression of anti-CD3-induced RANKL expression. In addition to its potential role in immune responses, RANKL expressed on activated T lymphocytes may provide a mechanism for the communication between the immune and skeletal systems during immune responses and disease states such as rheumatoid arthritis.

Taura S, Murata Y, Aung W, Ishida R, Zhang L, Hossain M, Takahashi Y, Okada N, Shibuya H. · Department of Radiology, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. · Clin Nucl Med. · Pubmed #11914666 No free full text.

Abstract: PURPOSE: The authors assessed the uptake of Tc-99m pertechnetate in the thyroid using salivary gland scintigraphy in patients with Sjögren syndrome and in healthy controls. MATERIALS AND METHODS: Salivary gland scintigraphy and a labial biopsy were performed in 73 patients with Sjögren syndrome. Based on the labial biopsy findings, 32 patients with a histopathologic grade of 1 or 2 were regarded as having early-stage Sjögren syndrome and 41 patients with a grade of 3 or 4 were regarded as having an advanced stage. After the administration of 370 MBq (10 mCi) Tc-99m pertechnetate, dynamic salivary gland scintigraphy was performed for 50 minutes. Lemon juice was used to stimulate the salivary glands, and the thyroid gland was included in the imaging area. Scintigraphy was also performed in an age- and sex-matched control group of 25 healthy persons. The thyroid uptake ratio was calculated for the scintigraphic images and compared among the three groups: healthy controls, patients with early-stage Sjögren syndrome, and those with advanced-stage Sjögren syndrome. RESULTS: When compared with the control group, the thyroid uptake ratio of the early-stage Sjögren syndrome group was not significantly different, whereas that of the advanced-stage group was significantly lower. CONCLUSIONS: Thyroid uptake of Tc-99m pertechnetate was less in patients with advanced-stage Sjögren syndrome than in patients with early-stage Sjögren syndrome or in healthy controls. Measuring the thyroid uptake of Tc-99m pertechnetate using salivary gland scintigraphy is an easy and useful method for assessing thyroid disorders in Sjögren syndrome and thus should be performed routinely.