ABSTRACT
AIM: Calcinosis is often observed in systemic sclerosis (SSc), but its pathogenesis remains unclear. The aim of the present study was to explore the association of clinical features with calcinosis in patients with SSc. METHODS: A retrospective cohort study was performed analyzing 416 SSc patients from our SSc database. We examined the clinical features with relation to calcinosis and SSc. RESULTS: Calcinosis was observed in 24.0% of patients with SSc. The group with calcinosis comprised more female patients (P < 0.05) and diffuse cutaneous types (P < 0.001) than the group without calcinosis. Complications of Raynaud's phenomenon (P < 0.05), nail fold bleeding (NFB) (P < 0.001), peripheral bone resorption (P < 0.001), myositis (P < 0.001), and pulmonary hypertension (P < 0.05) were more frequently observed in patients with calcinosis compared with those without calcinosis. The group with calcinosis had a higher modified Rodnan total skin-thickness score (mRSS) than the group without calcinosis (P < 0.001). The factors that affected calcinosis in multivariable analysis were peripheral bone resorption (partial correlation coefficient 0.46, 34%), anti-Scl-70 antibody (partial correlation coefficient 0.29, 20%), diffuse type (partial correlation coefficient 0.34, 16%) and NFB (partial correlation coefficient 0.23, 11.2%). CONCLUSIONS: Calcinosis in SSc is associated with Raynaud's phenomenon, NFB, and pulmonary hypertension, so peripheral circulatory insufficiency seems to be one of the causes of calcinosis. Furthermore, as it is related to mRSS and the diffuse cutaneous type, common factors related to skin fibrosis are considered to be involved.
Subject(s)
Calcinosis/complications , Scleroderma, Systemic/complications , Adult , Aged , Calcinosis/epidemiology , Female , Humans , Hypertension, Pulmonary/epidemiology , Japan/epidemiology , Male , Middle Aged , Raynaud Disease/epidemiology , Retrospective Studies , Scleroderma, Systemic/epidemiology , Skin/pathologyABSTRACT
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder accompanied by periodic fever and sterile serositis. We report a 5-year-old boy with FMF, who underwent second unrelated cord blood transplantation (CBT) for recurrent familial hemophagocytic lymphohistiocytosis. Periodic attacks of fever and abdominal pain started 6 months after CBT. He was diagnosed with FMF according to the Tel-Hashomer criteria and treated successfully with colchicine. Genetic testing showed heterozygous p.E148Q mutation in the MEFV gene from both donor and recipient cells. Several CBT-related factors including use of an immunosuppressant can potentially be involved in the pathogenesis of FMF in our patient.
Subject(s)
Cord Blood Stem Cell Transplantation/adverse effects , Familial Mediterranean Fever/pathology , Lymphohistiocytosis, Hemophagocytic/therapy , Mutation , Pyrin/genetics , Child, Preschool , Familial Mediterranean Fever/etiology , Humans , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/pathology , Male , PrognosisABSTRACT
AIM: Hypoxia-inducible factor (HIF)1α is induced by endothelial cells under hypoxic conditions, suggesting that HIF1α may be involved in vascular impairment in patients with systemic sclerosis (SSc). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to SSc and its complications, including pulmonary arterial hypertension (PAH). METHOD: This study involved 182 Japanese SSc patients (discovery cohort) and 178 healthy controls. Four SNPs (rs11549465, rs11549467, rs1957757, and rs12434438) of the HIF1A gene were genotyped using specific TaqMan probes. We also employed another SSc cohort (N = 135) to validate the significant results of SNPs found in the discovery SSc cohort. RESULTS: The frequencies of the four SNPs did not show any significant differences between the SSc and healthy control groups. The AA genotype at rs12434438 was significantly higher in SSc patients with PAH than in those without PAH (P = .012). These results were validated using another SSc cohort (N = 135, P = .006). Moreover, the AA genotype was significantly associated with the severity of PAH. CONCLUSION: Although HIF1A gene polymorphisms were not associated with susceptibility to SSc, the AA genotype at rs12434438 was associated with a subset of SSc patients with severe PAH, suggesting that the rs12434438 SNP may contribute to the development of PAH with SSc.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Polymorphism, Single Nucleotide , Pulmonary Arterial Hypertension/genetics , Scleroderma, Systemic/genetics , Adult , Aged , Case-Control Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Phenotype , Predictive Value of Tests , Pulmonary Arterial Hypertension/diagnosis , Reproducibility of Results , Risk Assessment , Risk Factors , Scleroderma, Systemic/complications , Scleroderma, Systemic/diagnosisABSTRACT
OBJECTIVES: This is a noncomparative study performed to determine if fever pattern is related to a diagnosis of autoinflammatory disease (AID) in pediatric- and adult-onset patients. METHODS: The final diagnosis of patients suspected to have AID was evaluated against gene polymorphisms known to be responsible for AID, clinical manifestations, and fever pattern, in our institute from 2005 to 2016. Genomic DNA was isolated from patients' peripheral blood, and polymerase chain reaction was used to amplify the indicated exons of 12 genes: MEFV, TNFRSF1A, MVK, NLRP3, NOD2, LI1RN, IL36RN, PSMB8, NALP12, PSTPIP1, TNFAIP3, and NLRC4. Genetic polymorphisms of the above genes were examined. RESULTS: All 210 individuals (135 pediatric onset and 75 adult onset) were classified into the following 3 subgroups: (1) periodic fever (n = 74 and 25 for pediatric and adult onset, respectively), (2) recurrent fever lacking a regular period (n = 47 and 41), and (3) persistent fever (n = 14 and 9). Diagnosis of AID was highest in subgroup 1 (70.2% and 36.0% for pediatric and adult onset, respectively), followed by subgroup 2(29.8% and 17.1%), including PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) (n = 34 and 1), familial Mediterranean fever (n = 22 and 13), cryopyrin-associated periodic syndrome (n = 6 and 1), and tumor necrosis factor receptor-associated periodic syndrome (n = 3 and 1 for pediatric and adult onset, respectively). None were diagnosed with AID in subgroup 3. CONCLUSIONS: Autoinflammatory disease was more likely to be diagnosed in pediatric-onset patients compared with adult-onset patients. In both age-onset groups, AID was primarily identified in patients with periodic fever and never diagnosed in patients with persistent fever. Our findings indicate that fever pattern is a useful factor to estimate the probability of AID.
Subject(s)
Familial Mediterranean Fever , Lymphadenitis , Pharyngitis , Stomatitis, Aphthous , Adult , Child , Familial Mediterranean Fever/diagnosis , Familial Mediterranean Fever/epidemiology , Familial Mediterranean Fever/genetics , Fever/diagnosis , Fever/epidemiology , Fever/etiology , HumansABSTRACT
OBJECTIVES: Palindromic rheumatism (PR) is a type of acute arthritis or periarthritis characterized by recurrence, paroxysmal, or intermittent disease attacks and occasionally progresses to other types of rheumatic disease. PR patients who are anti-citrullinated protein antibodies (ACPA)-negative have a high prevalence of MEFV gene polymorphisms, and intermittent hydrarthrosis (IH) is also associated with MEFV polymorphisms. The purpose of this study was to evaluate the clinical characteristics of and autoinflammatory syndrome-associated gene polymorphisms in patients with PR and IH and to identify predictive factors for developing other rheumatic diseases. METHODS: Six PR patients (four females; median age at disease onset, 20.0 years; median age at evaluation, 47.0 years) were retrospectively evaluated for clinical features and polymorphisms in genes responsible for autoinflammatory diseases. RESULTS: All six patients fulfilled the diagnostic criteria for PR and showed clinical feature of IH. Two presented with recurrent fever. All six patients were negative for rheumatoid factor and ACPA and had normal articular X-ray findings. Among the six patients, MEFV gene polymorphisms known to cause FMF were identified in four, CIAS1 mutation was observed in one, and TNFRSFIA mutation was observed in one. Colchicine was effective in three patients with MEFV polymorphisms. The other five patients continued to experience PR, although three patients achieved remission with medication. CONCLUSIONS: PR presenting with IH might be associated with gene polymorphisms responsible for autoinflammatory diseases; colchicine appears to be effective in these patients.Key Point⢠Palindromic rheumatism with intermittent hydrarthrosis might be associated with gene polymorphisms responsible for autoinflammatory diseases.
Subject(s)
Arthritis, Rheumatoid/genetics , Hydrarthrosis/genetics , Polymorphism, Genetic , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Rheumatoid/drug therapy , Colchicine/therapeutic use , Female , Genetic Predisposition to Disease , Humans , Hydrarthrosis/drug therapy , Male , Middle Aged , Mutation , Pyrin/genetics , Retrospective StudiesABSTRACT
Associations between anti-M-type phospholipase A2 receptor (PLA2R) antibodies and disease activity and prognosis have been suggested in primary membranous nephropathy (MN); however, more evidence is needed. We aimed to establish a clinically useful method to measure anti-PLA2R antibodies. We developed a western blot assay and a cell-based enzyme-linked immunosorbent assay (ELISA). Anti-PLA2R antibodies were evaluated retrospectively using these assays and the commercial solid-phase ELISA. Anti-PLA2R antibodies were detected in 12, 6, and 12 out of 23 Japanese patients with biopsy-proven primary MN using the western blot, the cell-based ELISA, and the solid-phase ELISA, respectively. The samples of the lupus MN patients tested negative. The levels of proteinuria correlated moderately with the titres of anti-PLA2R antibodies measured by the three methods (r = 0.39-0.47). Anti-PLA2R antibodies were significantly associated with physicians' decisions on immunosuppressive treatment without prior knowledge of anti-PLA2R antibody positivity (p < .01). In the longitudinal analysis, the titres of anti-PLA2R antibodies measured by the solid-phase ELISA declined significantly following treatment (p = .03). In conclusion, these results suggest the usefulness of anti-PLA2R antibody as a diagnostic, prognostic, and surrogate biomarker in primary MN. The three methods proved to be reliable for measuring anti-PLA2R antibody titres, but their performances differ.
Subject(s)
Antibodies/blood , Enzyme-Linked Immunosorbent Assay/methods , Glomerulonephritis, Membranous/diagnosis , Glomerulonephritis, Membranous/immunology , Receptors, Phospholipase A2/immunology , Biomarkers/blood , HumansABSTRACT
IL-35 is known as a regulatory cytokine produced by regulatory T cells. It has also been reported that IL-35 suppresses the proliferation of Th17 cells, which is involved in the pathogenesis of many autoimmune diseases. However, in rheumatoid arthritis patients, the role of IL-35 is controversial, and the role of IL-35 in bone metabolism has not been clarified. We investigated the effect of IL-35 on human osteoclast differentiation and activation. We first evaluated the effect of rhIL-35 on human osteoclastogenesis from monocytes cultured alone, induced by soluble-RANKL. We also examined the role of IL-35 on the bone-resorption function of mature osteoclasts. Furthermore, we analysed the molecular mechanism of IL-35 function in monocytes or pre-osteoclasts using RT-PCR. rhIL-35 significantly inhibited human osteoclastogenesis in a dose-dependent manner. In addition, rhIL-35 also significantly decreased the area of pit formation by mature osteoclasts. rhIL-35 significantly decreased mRNA expression of RANK in monocytes and RANK and FOS in pre-osteoclasts. Our current findings suggest that IL-35 inhibits osteoclastogenesis and osteoclast activation by inhibiting both RANK and FOS. IL-35 also has an inhibitory effect on osteoclastic-bone resorption, suggesting that IL-35 may have a therapeutic potential for RA.
ABSTRACT
BACKGROUND: Clusters of autoimmune diseases (ADs) are present in some people with type 1 diabetes. This clustering suggests the existence of common genetic backgrounds for abnormal autoimmunity in these individuals. However, the genetic differences between type 1 diabetes patients with and without other ADs are not well known. METHODS: To investigate the clinical background and genetic differences between type 1 diabetes patients with and without other ADs, single nucleotide polymorphisms (SNPs) in the CTLA4, SUMO4, PTPN22, IRF5, STAT4, and BLK genes were analysed by using either a TaqMan assay or direct sequencing. The frequencies of alleles, genotypes of each gene, and the human leukocyte antigen (HLA) haplotype were analysed to investigate differences among 3 groups: type 1 diabetes with systemic ADs (group A), type 1 diabetes with other organ-specific ADs (group B), and type 1 diabetes without other ADs (group C). RESULTS: The frequency of the C allele in the -1123G > C SNP in the PTPN22 gene promoter was significantly higher in groups A and B than in group C (P = .0258 and .0207, respectively). The allele frequencies of the other SNPs were comparable. The frequency of HLA DRB1*0405-DQB1*0401 was significantly higher in groups A and B than in group C (P = .021 and .0395, respectively). CONCLUSIONS: The -1123G > C SNP in the PTPN22 gene promoter and HLA DRB1*0405-DQB1*0401 might influence the concurrence of systemic and organ-specific ADs in patients with type 1 diabetes.
Subject(s)
Autoimmune Diseases/complications , Autoimmune Diseases/genetics , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Adult , Aged , CTLA-4 Antigen/genetics , Diabetes Mellitus, Type 1/immunology , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , HLA-DQ beta-Chains/genetics , HLA-DRB1 Chains/genetics , Humans , Middle Aged , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Small Ubiquitin-Related Modifier Proteins/genetics , Young AdultABSTRACT
IL-23, which is composed of p19 and p40 subunits, is a proinflammatory cytokine that contributes to the formation and maintenance of Th17 cells in inflammatory autoimmune diseases. IL-23 is a human osteoclastogenic cytokine and anti-IL-23 antibody attenuates paw volume and joint destruction in CIA rats. IL-23 levels in serum and synovial fluid are high in rheumatoid arthritis (RA) patients, and IL-23 may be a useful biomarker for the diagnosis of RA. In addition, IL-23 affects the pathogenesis of inflammation and bone destruction through interaction with other cytokines such as IL-17 and TNF-α. Furthermore, polymorphisms of IL23R are a risk factor for ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which indicates that IL-23 is also involved in the pathogenesis of spondyloarthritis (SpA). Finally, IL-17 and IL-23 inhibitors reduce the clinical manifestations of SpA. Thus, the IL-23/Th17 pathway is a therapeutic target for the treatment of inflammatory arthritis.
ABSTRACT
Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis.
Subject(s)
Alanine/analogs & derivatives , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Osteoclasts/cytology , Osteoclasts/drug effects , Osteogenesis/drug effects , Quinolones/administration & dosage , Alanine/administration & dosage , Analgesics/administration & dosage , Cell Proliferation/drug effects , Cell Proliferation/physiology , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Hydroquinones/administration & dosage , Leukocytes, Mononuclear/physiology , Osteoclasts/physiology , Osteogenesis/physiologyABSTRACT
Objective: Th17 cells, which mainly produce interleukin (IL)-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. The plasticity of Th17 cells, in which these cells shift to a Th1 phenotype in the presence of IL-12, has recently been reported. However, the role of IL-17 in Sjögren's syndrome (SS) and Mikulicz's disease (MD) currently remains unknown. PATIENTS AND METHODS: The submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients were collected. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected by immunohistochemical staining. RESULTS: IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected in the submandibular salivary gland and lymph node of the MD patient and salivary glands of the 15 SS patients. DISCUSSION: IFN-γ+IL-17+cells in the salivary glands of patients were speculated to be Th1/Th17 cells in the present study. Th1/Th17 cells are known to be derived from Th17 cells and differentiate into Th1 cells, and IL-17-derived Th1 cells have been suggested to induce the deterioration of juvenile idiopathic arthritis (JIA). Thus, Th1/Th17 cells may play an important role in the pathogenesis of SS and MD. CONCLUSION: IFN-γ+, IFN-γ+IL-17+, and IL-17+ cells were detected in the submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients.
Subject(s)
Cell Plasticity/immunology , Mikulicz' Disease/immunology , Salivary Glands/cytology , Salivary Glands/immunology , Sjogren's Syndrome/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Adult , Aged , Arthritis, Juvenile/immunology , Arthritis, Juvenile/pathology , Cell Differentiation , Female , Humans , Immunohistochemistry , Interferon-gamma/biosynthesis , Interleukin-12/immunology , Interleukin-17/biosynthesis , Lymph Nodes/cytology , Lymph Nodes/immunology , Middle Aged , Mikulicz' Disease/pathology , Sjogren's Syndrome/pathology , Th17 Cells/cytology , Th17 Cells/metabolismABSTRACT
Rheumatoid arthritis (RA) appears as inflammation of synovial tissue and joint destruction. Receptor activator of NF-κB (RANK) is a member of the TNF receptor superfamily and a receptor for the RANK ligand (RANKL). In this study, we examined the expression of RANKhigh and CCR6 on CD14+ monocytes from patients with RA and healthy volunteers. Peripheral blood samples were obtained from both the RA patients and the healthy volunteers. Osteoclastogenesis from monocytes was induced by RANKL and M-CSF in vitro. To study the expression of RANKhigh and CCR6 on CD14+ monocytes, two-color flow cytometry was performed. Levels of expression of RANK on monocytes were significantly correlated with the level of osteoclastogenesis in the healthy volunteers. The expression of RANKhigh on CD14+ monocyte in RA patients without treatment was elevated and that in those receiving treatment was decreased. In addition, the high-level expression of RANK on CD14+ monocytes was correlated with the high-level expression of CCR6 in healthy volunteers. Monocytes expressing both RANK and CCR6 differentiate into osteoclasts. The expression of CD14+RANKhigh in untreated RA patients was elevated. RANK and CCR6 expressed on monocytes may be novel targets for the regulation of bone resorption in RA and osteoporosis.
Subject(s)
Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/metabolism , Monocytes/metabolism , Osteoclasts/metabolism , Osteogenesis , Receptor Activator of Nuclear Factor-kappa B/metabolism , Adult , Aged , Case-Control Studies , Cell Count , Fluorescence , Humans , Lipopolysaccharide Receptors/metabolism , Middle Aged , Receptors, CCR6/metabolismABSTRACT
Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17(+)Th17 cells, and IFNγ (+)Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ (+)Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies.
Subject(s)
Arthritis, Rheumatoid/immunology , Interferon-gamma/blood , Interleukin-17/blood , Peptides, Cyclic/blood , Aged , Antibodies, Anti-Idiotypic/immunology , Antibodies, Anti-Idiotypic/therapeutic use , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/pathology , Female , Gene Expression Regulation , Humans , Interferon-gamma/immunology , Interleukin-17/immunology , Interleukin-17/therapeutic use , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily B/blood , Peptides, Cyclic/immunology , T-Lymphocytes, Helper-Inducer/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Th17 Cells/metabolismABSTRACT
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161(+)Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161(+)Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase.
Subject(s)
Arthritis, Rheumatoid/immunology , Interleukin-17/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Adult , Age of Onset , Aged , Antibodies, Anti-Idiotypic , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/therapy , Female , Humans , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily B/blood , NK Cell Lectin-Like Receptor Subfamily B/immunologyABSTRACT
In 2011, St Hilaire et al (N Engl J Med. 2011;364:432-442) identified mutations in the ecto-5'-nucleotidase (NT5E) gene, which encodes CD73, in members of 3 families with symptomatic arterial and joint calcifications. The deficiency of CD73 involves the extracellular adenosine metabolism that influences inorganic pyrophosphate and phosphate metabolism and leads to tissue calcification. Herein, we report an additional case with arterial calcification due to deficiency of CD73. Genetic analyses revealed that the patient was a compound heterozygote of mutations in the NT5E gene. The present case had intermittent monoarthritis of the finger joints and early-onset osteoarthritis in the hands. Occlusion of calcified peripheral arteries is the most important outcome of the disease. However, the rheumatic manifestations may be important clues to the diagnosis. Rheumatologists should recognize deficiency of CD73 as a rheumatic disease.
Subject(s)
5'-Nucleotidase/genetics , Calcinosis/genetics , Joint Diseases/genetics , Rheumatic Diseases/genetics , Vascular Diseases/genetics , Adult , Calcinosis/diagnostic imaging , Female , GPI-Linked Proteins/genetics , Humans , Joint Diseases/diagnostic imaging , Radiography , Rheumatic Diseases/diagnostic imaging , Vascular Diseases/diagnostic imagingABSTRACT
BACKGROUND: We have demonstrated that a peptide, which we named 'Peptide A', derived from the extracellular domain of T-cell leukemia translocation-associated gene (TCTA) protein, inhibited human osteoclastogenesis. OBJECTIVE: In the current study, we examined whether this peptide inhibits the proliferation of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) or not. MATERIAL AND METHODS: Fibroblast-like synoviocytes obtained from five RA patients were cultured in the absence or presence of 1, 5, 10 µg/ml of peptide. We used 29-mer scrambled peptide as a control. RESULTS: The peptide inhibited the proliferation of RA FLS dose-dependently. On the other hand, the scrambled peptide showed no inhibition. CONCLUSIONS: The peptide inhibits both human osteoclastogenesis and the proliferation of RA FLS. Thus, the peptide may be used for the therapy of both osteoporosis and synovitis of RA patients. This is the first report of the new peptide we discovered, which inhibits both osteoclastogenesis and synovitis. Thus, this new peptide could be a new drug for patients with both osteoporosis and RA.
ABSTRACT
Fewer molecules have been identified on human than murine osteoclasts, the former differing from murine osteoclasts in many ways. We show that voltage-dependent anion channels (VDACs, porin) are expressed in the plasma membrane of human osteoclasts. A search for novel proteins expressed in the plasma membrane of human osteoclasts identified VDAC. Anti-VDAC antibodies inhibited human osteoclastogenesis in vitro. VDAC expression was detected in membranes by immunoelectron microscopy and immunocytochemical double staining. The VDAC protein functions as a Cl(-) channel. VDACs regulate bone resorption, which show using Osteologic™ plates. The epitope of the antibody lay within a 10-amino acid sequence in the VDAC. The findings suggest that the VDAC is, at least partly, a novel Cl(-) channel regulating the differentiation and function of human osteoclasts. VDACs may play a crucial role in acidifying the resorption lacunae between osteoclasts and bone. Inhibitors of VDACs could be used to treat diseases involving increased resorption, such as osteoporosis, rheumatoid arthritis, and Paget's disease.
Subject(s)
Cell Differentiation , Cell Membrane/metabolism , Osteoclasts/cytology , Voltage-Dependent Anion Channels/metabolism , Amino Acid Sequence , Animals , Female , Humans , Mice , Microscopy, Immunoelectron , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Osteoclasts/metabolism , RANK Ligand/genetics , RANK Ligand/metabolismSubject(s)
Arthritis, Rheumatoid/genetics , Asian People/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Arthritis, Rheumatoid/ethnology , Asian People/ethnology , Case-Control Studies , Female , Humans , Japan/ethnology , Lupus Erythematosus, Systemic/ethnology , Lupus Erythematosus, Systemic/genetics , Male , Middle Aged , Scleroderma, Systemic/ethnology , Scleroderma, Systemic/geneticsABSTRACT
Mouse receptor activator of NF-κB ligand (RANKL), which induces osteoclastogenesis from monocytes or macrophages, was independently cloned by three groups in 1997. Mouse osteoclasts have been induced from peripheral monocytes stimulated by RANKL and macrophage colony-stimulating factor (M-CSF) both in vitro and in vivo; however, the mechanism of primate osteoclastogenesis has not been studied. In addition, the effects of human RANKL on primate osteoclastogenesis remain to be elucidated. Here, we investigated the effect of human RANKL on the osteoclastogenesis of monocytes from five subspecies of primates. Human RANKL induced osteoclastogenesis of all the primates. In addition, human RANKL induced pit formation by osteoclasts from monocytes of the crab-eating macaque. We also demonstrated that the primate osteoclastogenesis was inhibited by a novel peptide, which inhibited human osteoclastogenesis in our previous study. Thus, these findings clearly demonstrated that human RANKL induces primate osteoclastogenesis in the presence of human M-CSF.
Subject(s)
Monocytes/drug effects , Osteoclasts/drug effects , Primates , RANK Ligand/pharmacology , Animals , Bone Resorption/physiopathology , Cell Culture Techniques , Cell Differentiation , Humans , Macrophage Colony-Stimulating Factor/pharmacology , Monocytes/cytology , Oncogene Protein pp60(v-src)/pharmacology , Peptide Fragments/pharmacologyABSTRACT
Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection.