Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated T cells, through the production of the receptor activator of NF-kappaB ligand (RANKL) cytokine, have been implicated in the osteoclast development and bone loss that are associated with autoimmune diseases such as rheumatoid arthritis. However, the cellular pathways that regulate the expression of RANKL and the induction of osteoclasts are still unclear. In this study, we show that, in human effector CD4(+) T cells, activation of alpha1beta1 integrin and interleukin (IL)-7 receptor (IL-7R) up-regulates the expression and production of RANKL but has no effect on the production of interferon-gamma, an inhibitor of T-cell-mediated osteoclastogenesis. Thus, both alpha1beta1 integrin and IL-7R enhance the ability of these cells to induce the formation of osteoclasts from human monocytes. Furthermore, we found that simultaneous activation of effector CD4(+) T cells via alpha1beta1 integrin and IL-7R synergistically increases the production of RANKL and enhances their osteoclastogenic function. We also show that, although alpha1beta1 integrin does not protect human effector CD4(+) T cells from IL-2-withdrawal-induced apoptosis, it does enhance the pro-survival effect of IL-7, further emphasizing the importance of the alpha1beta1/IL-7R synergistic effect. Together our results identify a new function of alpha1beta1 integrin in T cells and suggest that activation of effector CD4(+) T cells through alpha1beta1 integrin and IL-7R is an important regulatory pathway in T-cell-dependent osteoclastogenesis. Further understanding of the mechanisms by which IL-7R and alpha1beta1 integrin promote T-cell-mediated osteoclastogenesis will lead to new insights into the regulatory pathways of T-cell-dependent bone resorption associated with autoimmune diseases.
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PMID:Alpha1beta1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T cells and enhance their osteoclastogenic function. 1847 50

Inflammation-mediated bone loss is a major feature of various bone diseases including rheumatoid arthritis, osteoarthritis and advanced periodontitis. Enhanced osteoclast development or activity at the inflammation site results in bone resorption. IL-23 is a heterodimeric cytokine belonging to the IL-6/IL-12 family that has been implicated in the pathogenesis of rheumatoid arthritis and demonstrated to play a role in osteoclastogenesis via stimulation of IL-17 production. In this study we investigated whether IL-23 contributes to the regulation of osteoclast differentiation independent of the IL-17 pathway. We show that IL-23 dose-dependently up-regulates receptor activator of NF-kappaB expression in primary murine bone marrow macrophages and RAW264.7 cells and thereby promotes commitment of myeloid precursor cells to receptor activator of NF-kappaB ligand-mediated osteoclastic differentiation. However, IL-23 by itself is insufficient to induce osteoclastogenesis. Increased osteoclastic differentiation of cells was associated with enhanced cathepsin K expression and dentine resorption indicating enhanced formation of functional osteoclasts. IL-17 was not detectable in culture supernatants and when added to cultures, did not promote differentiation of RAW264.7 cells. These results demonstrate that IL-23 can act directly on myeloid precursor cells in addition to indirectly stimulating receptor activator of NF-kappaB ligand production in osteoblasts and explains its potency in driving osteoclast development in inflammation-mediated bone pathology.
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PMID:IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. 1895 85

RNA interference (RNAi) provides a powerful means of sequence-specific gene silencing. Several studies show that RNAi may provide promising strategies to treat human diseases by suppressing disease responsible genes in vivo. In locomotor diseases, the progression of collagen-induced arthritis (CIA) is suppressed by tumor necrosis factor-alpha (TNF-alpha)-specific small interfering RNA (siRNA) delivered into the joint. The aim of this study, is to compare the effects of intraarticularly administered siRNAs targeting TNF-alpha, interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and receptor activator of NF-kappaB ligand (RANKL) on CIA in rats. We confirmed that the silencing effects of siRNA duplexes specific for rat TNF-alpha, IL-1beta, IL-6 and RANKL in vitro. Each siRNA was also delivered into the knee joint of CIA rats by the in vivo electroporation method 7, 10, 13 and 16 days after immunization with collagen. Local delivery of TNF-alpha or IL-1beta-specific siRNA ameliorated CIA in rats effectively at the gross morphological, radiographical and histological evaluations. Our results suggested that TNF-alpha and IL-1beta were the cytokines to be targeted in the joint for the treatment of rheumatoid arthritis. The in vivo siRNA transfection method may be useful for selection of target molecules to be silenced for treatment of joint diseases.
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PMID:Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets. 1903 Jul 78

CXCL10 is a 10 kDa protein, which is categorized functionally as a Th1-chemokine. It binds to the receptor CXCR3 and regulates immune responses through the activation and recruitment of leukocytes, such as, T cells, eosinophils, and monocytes. Recent reports have shown that serum and/or tissue expressions of CXCL10 are increased in various autoimmune diseases like rheumatoid arthritis (RA), systemic lupus rythematosus (SLE), Sjogren syndrome (SS), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM). Moreover, CXCL10 and CXCR3 may have important roles in leukocyte homing to inflamed tissues and in the perpetuation of inflammation, and therefore, tissue damage. Our recent study shows that CXCL10 also has a pathogenic role in bone destruction via receptor activator of NF-kappaB ligand (RANKL) induction in inflamed synovial tissue of RA. In addition to its chemotactic effect, CXCL10 may have pleiotropic functions. Further research on the function of this chemokine and interactions between CXCL10 and other cytokines and chemokines may provide therapeutic targets in various autoimmune diseases.
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PMID:CXCL10 and autoimmune diseases. 1910 84

Mizoribine is a disease-modifying anti-rheumatic drug (DMARD) that is used in the treatment of rheumatoid arthritis. However, clinical use of the drug is restricted to a few Asian countries due to a lack of comprehensive evidence on its effectiveness. The inhibitory effect of the drug on human osteoclastogenesis was investigated in the hopes of providing some clear evidence. Mizoribine was found to inhibit in vitro osteoclastogenesis in a dose-dependent manner. In addition, the size of the pit area was closely related to the number of osteoclasts in a bone resorption assay. However, mizoribine did not affect the phosphorylation of MAP kinase (p38, JNK, ERK), the degradation of IkappaBalpha, or receptor activator of NF-kappaB ligand (RANKL) expression in fibroblast-like synoviocytes stimulated with IL-1beta. These results suggested that mizoribine may partially suppress osteoclastogenesis, leading to progressive bone erosion by inhibiting the growth or the signaling pathway of precursor cells to form osteoclasts rather than fibroblast-like synoviocytes.
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PMID:Mizoribine may suppress bone erosion in patients with rheumatoid arthritis by inhibiting osteoclastogenesis. 1917 Nov 30

In rheumatoid arthritis, T cells activation enhances osteoclast differentiation and bone destruction through receptor activator of NF-kappaB ligand (RANKL) . Recent study revealed the importance of interleukin-17 (IL-17) -producing helper T cell subset (Th17) in bone destruction. The emerging field of osteoimmunology will be of great importance not only to the better understanding of osteoclast differentiation and activation but also to the regulation of inflammation-associated bone destruction.
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PMID:[Molecular mechanism of bone destruction]. 1925 43

Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4(+) T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4(+)CD25(-) T cells produce IL-21. We generated IL-21R-deficient (IL-21R(-/-)) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4(+) T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1(+) memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-kappaB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R(-/-) K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4(+) cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.
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PMID:A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. 1934 40

Mesenchymal stem cells (MSCs) are characterized by their hematopoiesis-supporting and immunosuppressive capacity, while osteoclasts are main cell components in the endosteal hematopoietic stem cell niche and pivotal players in osteoimmunology. To clarify the association of these 2 kinds of cells, mouse CD11b(+) monocytes were cultured onto MSC layers in the presence or absence of macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). The results showed that MSCs independently supported osteoclast development and this effect was enhanced by M-CSF and RANKL. Interestingly, tumor necrosis factor-alpha (TNF-alpha)-stimulated MSCs turned to inhibit osteoclast formation and protect tusk slices from osteoclastic resorption. Real-time PCR and ELISA assays demonstrated that osteoprotegerin expression at both mRNA and protein levels in TNF-alpha-stimulated MSCs was up-regulated, at least partially by activating the mitogen-activated protein kinase pathway. Furthermore, TNF-alpha-stimulated MSCs maintained their immunophenotypic, multipotential differentiation and immunosuppressive characteristics. Moreover, MSCs treated with synovial fluid from rheumatoid arthritis patients modulated osteoclast generation in close relation with the TNF-alpha levels. This study suggests that MSCs exhibit dual modulatory function on osteoclasts and the result might shed light on understanding the involvement of MSCs in the inflammatory diseases.
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PMID:Tumor necrosis factor-alpha alters the modulatory effects of mesenchymal stem cells on osteoclast formation and function. 1937 89

Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4(+)CD45RO(+)FoxP3(+) regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-gamma production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-kappaB ligand (RANKL), lack of IFN-gamma response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity.
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PMID:Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. 1938 Aug

This study was undertaken to determine the effect of toll-like receptor-3 (TLR3) on the regulation of osteoclastogenic activity in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). The expression of receptor activator of nuclear factor kappa B ligand (RANKL) mRNA and protein in RA-FLS after TLR3 activation was determined using RT-PCR, real-time PCR, western blot analysis, and immunohistochemistry. Human monocytes were cocultured with RA-FLS that had been prestimulated by the TLR3 ligand polyriboinosinic-polyribocytidylic acid and then stained for tartrate-resistant acid phosphatase (TRAP) activity. Other markers of osteoclasts were measured using RT-PCR and real-time PCR. The expression of TLR3 and RANKL was much higher in the RA synovium than in the osteoarthritis (OA) synovium. TLR3 activation induced RANKL expression in RA-FLS, but not in OA-FLS or in normal skin fibroblasts. TLR3 activation also induced the production of IL-1beta but had no effect on IL-17 or TNF-alpha production in RA-FLS. Inhibition of IL-1beta reversed the TLR3-induced upregulation of RANKL expression. Coculture of human monocytes with TLR3-activated RA-FLS or TLR3 ligand-stimulated human monocytes increased the expression of TRAP, RANK, cathepsin K, calcitonin receptor, and MMP-9, reflecting the differentiation of monocytes into osteoclasts. Our results suggest that TLR3 promotes osteoclastogenesis in the RA synovium both directly and indirectly. TLR3 stimulates human monocytes directly to promote osteoclast differentiation. TLR3 induces RANKL expression indirectly in RA-FLS, and the expression of RANKL promotes the differentiation of osteoclasts in the RA synovium. Targeting the TLR3 pathway may be a promising approach to preventing inflammatory bone destruction in RA.
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PMID:TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. 1944 44


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