Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efforts to therapeutically stimulate or inhibit vessel growth have been primarily focused on vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1), while little attention has been devoted to the therapeutic potential for angiogenic disorders of placental growth factor (PlGF), a VEGF family member, and its receptor VEGFR-1 (Flt-1). However, recent developments and insights could shift that focus to P1GF and Flt-1. Indeed, PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to VEGF and did not cause side effects associated with VEGF, such as edema or hypotension. An anti-Flt-1 antibody suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in arthritis. The anti-Flt-1 antibody also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not due to reduced plaque neovascularization. The anti-inflammatory effects of the anti-Flt-1 antibody were attributable to a reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood, a reduced mobilization/differentiation (and impaired infiltration) of Flt-1-expressing leukocytes into inflamed tissues, and a defective activation of myeloid cells. Thus, PlGF and Flt-1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
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PMID:Placental growth factor (PlGF) and its receptor Flt-1 (VEGFR-1): novel therapeutic targets for angiogenic disorders. 1254 19

Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.
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PMID:Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library. 1519 67

Vascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1/Flt-1) were shown to be involved in pathological angiogenesis, particularly rheumatoid arthritis (RA). However, the molecular basis of their actions is not fully understood. Here we report that in a murine model of RA, deletion of the tyrosine kinase (TK) domain of VEGFR-1 decreased the incidence and clinical symptoms of RA. Pathological symptoms, such as synovial hyperplasia, inflammatory infiltrates, pannus formation, and cartilage/bone destruction, became milder in Vegfr-1 tk(-/-) mice compared with wild-type (Wt) mice in the human T-cell leukemia virus-1 (HTLV-1) pX-induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in immunologic reactions such as phagocytosis and the secretion of interleukin-6 (IL-6) and VEGF-A. Treatment of this RA model with a small molecule inhibitor for VEGFR TK, KRN951, also attenuated the arthritis. These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA.
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PMID:Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. 1670 27

Vascular endothelial growth factor (VEGF) promotes cartilage-degrading pathways, and there is evidence for the involvement of reactive oxygen species (ROS) in cartilage degeneration. However, a relationship between ROS and VEGF has not been reported. Here, we investigate whether the expression of VEGF is modulated by ROS. Aspirates of synovial fluid from patients with osteoarthritis (OA) were examined for intra-articular VEGF using ELISA. Immortalized C28/I2 chondrocytes and human knee cartilage explants were exposed to phorbol myristate acetate (PMA; 0-20 microg/ml), which is a ROS inducer, or 3-morpholino-sydnonimine hydrochloride (SIN-1; 0-20 microM), which is a ROS donor. The levels of VEGF protein and nitric oxide (NO) production were determined in the medium supernatant, using ELISA and Griess reagent, respectively. Gene expression of VEGF-121 and VEGF-165 was determined by splice variant RT-PCR. Expression of VEGF and VEGF receptors (VEGFR-1 and VEGFR-2) was quantified by real-time RT-PCR. Synovial fluid from OA patients revealed markedly elevated levels of VEGF. Common RT-PCR revealed that the splice variants were present in both immortalized chondrocytes and cartilage discs. In immortalized chondrocytes, stimulation with PMA or SIN-1 caused increases in the levels of VEGF, VEGFR-1 and VEGFR-2 mRNA expression. Cartilage explants produced similar results, but VEGFR-1 was only detectable after stimulation with SIN-1. Stimulation with PMA or SIN-1 resulted in a dose-dependent upregulation of the VEGF protein (as determined using ELISA) and an increase in the level of NO in the medium. Our findings indicate ROS-mediated induction of VEGF and VEGF receptors in chondrocytes and cartilage explants. These results demonstrate a relationship between ROS and VEGF as multiplex mediators in articular cartilage degeneration.
Arthritis Res Ther 2006
PMID:Reactive oxygen species induce expression of vascular endothelial growth factor in chondrocytes and human articular cartilage explants. 1718 82

Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.
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PMID:Antiangiogenic agents: an update on small molecule VEGFR inhibitors. 1797 3

Angiogenesis is a complex biological phenomenon crucial for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process confined to the uterus and ovary during the different phases of the menstrual cycle and to the heart and skeletal muscles after prolonged and sustained physical exercise. Conversly, angiogenesis is one of the major pathological changes associated with several complex diseases like cancer, atherosclerosis, arthritis, diabetic retinopathy and age-related macular degeneration. Among the several molecular players involved in angiogenesis, some members of VEGF family, VEGF-A, VEGF-B and placenta growth factor (PlGF), and the related receptors VEGF receptor 1 (VEGFR-1, also known as Flt-1) and VEGF receptor 2 (VEGFR-2, also known as Flk-1 in mice and KDR in human) have a decisive role. In this review, we describe the discovery and molecular characteristics of PlGF, and discuss the biological role of this growth factor in physiological and pathological conditions.
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PMID:The discovery of placenta growth factor and its biological activity. 2222 76

The vascular endothelial growth factor (VEGF)-VEGF receptor (R) system is deeply involved in angiogenesis and lymphangiogenesis. VEGFR1/ Fms-like tyrosine kinase-1 (Flt-1) and VEGFR2 are significantly expressed in vascular endothelial cells, where they transfer proangiogenic signals. Particularly, VEGFR2 has strong tyrosine kinase activity; thus, the major and direct angiogenic signals are generated from VEGFR2. VEGFR3 is specifically expressed in lymphatic endothelial cells, generating the main signal for lymphangiogenesis. In addition, VEGFR1 is wellexpressed on the membrane of macrophage lineage cells such as monocytes, transducing an important signal for the migration and cytokine/chemokine production of these cells. This VEGFR1-macrophage axis stimulates seemingly non-inflammatory and inflammatory responses in various tissues and promotes a variety of diseases such as tumor growth via proangiogenesis, tumor metastasis, lymphangiogenesis, arthritis, and atherosclerosis. This axis is also important for the physiological recovery systems like bone marrow reconstitution and wound healing. VEGFR1 expresses two forms of mRNA: one for the full-length VEGFR1/Flt-1 receptor with tyrosine kinase; the other for a soluble form carrying only the ligand-binding region (sFlt-1/soluble VEGFR1) that functions as a decoy receptor by trapping its ligands VEGF-A, PlGF, and VEGF-B. Therefore, the VEGFR1-dependent inflammatory and non-inflammatory reactions are also regulated by a balance of gene expression between full-length and soluble forms of VEGFR1/Flt-1. Taken together, these findings suggest that VEGF-VEGFR signal is an important target for suppressing various diseases including inflammation.
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PMID:VEGF-VEGFR System as a Target for Suppressing Inflammation and other Diseases. 2577 79

The tyrosine kinase receptor, EphB4, mediates cross-talk between stromal and hematopoietic populations during bone remodeling, fracture repair and arthritis, through its interactions with the ligand, ephrin-B2. This study demonstrated that transgenic EphB4 mice (EphB4 Tg), over-expressing EphB4 under the control of collagen type-1 promoter, exhibited higher frequencies of osteogenic cells and hematopoietic stem/progenitor cells (HSC), correlating with a higher frequency of long-term culture-initiating cells (LTC-IC), compared with wild type (WT) mice. EphB4 Tg stromal feeder layers displayed a greater capacity to support LTC-IC in vitro, where blocking EphB4/ephrin-B2 interactions decreased LTC-IC output. Similarly, short hairpin RNA-mediated EphB4 knockdown in human bone marrow stromal cells reduced their ability to support high ephrin-B2 expressing CD34(+) HSC in LTC-IC cultures. Notably, irradiated EphB4 Tg mouse recipients displayed enhanced bone marrow reconstitution capacity and enhanced homing efficiency of transplanted donor hematopoietic stem/progenitor cells relative to WT controls. Studies examining the expression of hematopoietic supportive factors produced by stromal cells indicated that CXCL12, Angiopoietin-1, IL-6, FLT-3 ligand, and osteopontin expression were more highly expressed in EphB4 Tg stromal cells compared with WT controls. These findings indicate that EphB4 facilitates stromal-mediated support of hematopoiesis, and constitute a novel component of the HSC niche.
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PMID:EphB4 Expressing Stromal Cells Exhibit an Enhanced Capacity for Hematopoietic Stem Cell Maintenance. 2603 76