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Boldeanu MV, Boldeanu L, Cristea OM, Ciobanu DA, Poenariu SI, Dijmărescu AL, Bărbulescu AL, Pădureanu V, Sas TN, Dinescu ȘC, Vreju FA, Popoviciu HV, Ionescu RA. MMP-13, VEGF, and Disease Activity in a Cohort of Rheumatoid Arthritis Patients. Diagnostics (Basel) 2023; 13:diagnostics13091653. [PMID: 37175043 PMCID: PMC10184131 DOI: 10.3390/diagnostics13091653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Identifying certain serum biomarkers associated with the degree of rheumatoid arthritis (RA) activity can provide us with a more accurate view of the evolution, prognosis, and future quality of life for these patients. Our aim was to analyze the presence and clinical use of matrix metalloproteinase-13 (MMP-13), along with vascular endothelial growth factor (VEGF) and well-known cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) for patients with RA. We also wanted to identify the possible correlations between MMP-13 and these serological markers, as well as their relationship with disease activity indices, quality of life, and ultrasonographic evaluation. For this purpose, we analyzed serum samples of 34 RA patients and 12 controls. In order to assess serum concentrations for MMP-13, VEGF, TNF-α, and IL-6, we used the enzyme-linked immunosorbent assay (ELISA) technique. Our results concluded that higher levels of MMP-13, VEGF, TNF-α, and IL-6 were present in the serum of RA patients compared to controls, with statistical significance. We furthermore identified moderately positive correlations between VEGF, MMP-13, and disease activity indices, as well as with the ultrasound findings. We also observed that VEGF had the best accuracy (97.80%), for differentiating patients with moderate disease activity. According to the data obtained in our study, that although MMP-13, TNF-α and C-reactive protein (CRP) have the same sensitivity (55.56%), MMP-13 has a better specificity (86.67%) in the diagnosis of patients with DAS28(4v) CRP values corresponding to moderate disease activity. Thus, MMP-13 can be used as a biomarker that can differentiate patients with moderate or low disease activity. VEGF and MMP-13 can be used as additional parameters, along with TNF-α and IL-6, that can provide the clinician a better picture of the inflammatory process, disease activity, and structural damage in patients with RA. Our data can certainly constitute a start point for future research and extended studies with multicenter involvement, to support the selection of individualized and accurate therapeutic management strategies for our patients.
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Affiliation(s)
- Mihail Virgil Boldeanu
- Department of Immunology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Lidia Boldeanu
- Department of Microbiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Oana Mariana Cristea
- Department of Microbiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dana Alexandra Ciobanu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Sabin Ioan Poenariu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anda Lorena Dijmărescu
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Andreea Lili Bărbulescu
- Department of Pharmacology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Vlad Pădureanu
- Department of Internal Medicine, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Teodor Nicuşor Sas
- Department of Radiology and Imaging, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Ștefan Cristian Dinescu
- Department of Rheumatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Florentin Ananu Vreju
- Department of Rheumatology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Horațiu Valeriu Popoviciu
- Department of Rheumatology, BFK and Medical Rehabilitation, University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540139 Targu Mures, Romania
| | - Răzvan Adrian Ionescu
- Third Internal Medicine Department, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Zhang F, Liu Z, He X, Li Z, Shi B, Cai F. β-Sitosterol-loaded solid lipid nanoparticles ameliorate complete Freund's adjuvant-induced arthritis in rats: involvement of NF-кB and HO-1/Nrf-2 pathway. Drug Deliv 2021; 27:1329-1341. [PMID: 32945205 PMCID: PMC7534215 DOI: 10.1080/10717544.2020.1818883] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Rheumatoid arthritis (RA), autoimmune disease that is categorized via chronic
inflammation manifestation, obesity, cardiovascular risk and even enhanced the mortality
and affect the 0.3 and 1% of population worldwide. The current experimental study was
scrutinize the anti-arthritic effect of β-sitosterol loaded solid lipid nanoparticles
(SLN) against complete Fruend adjuvant (CFA)-induced arthritis via dual pathway. Double
emulsion solvent displacement method was used for the preparation of β-sitosterol solid
lipid nanoparticles (SLN). CFA was used to induce arthritis and rats were divided into
different groups for 28 days. Biochemical, anti-inflammatory, pro-inflammatory cytokines
and inflammatory mediator were estimated, respectively. Receptor activator of nuclear
factor kappa-B ligand (RANKL), signal transducer and activator of transcription-3 (STAT3)
nuclear factor erythroid 2–related factor 2 (Nrf2), Heme Oxygenase-1(HO-1) and
Nuclear factor-κB (NF-κB) expression were estimated. β-sitosterol-SLN significantly
(p < .001) reduced the paw edema, arthritic index and
increased the body weight. β-sitosterol-SLN increased the redox status of synovium {reduce
the malonaldehyde (MDA) and increase superoxide dismutase (SOD), glutathione (GSH) and
catalase (CAT)} level and reduced the cytokines such as tumor necrosis factor-α (TNF-α),
interleukin-1β (IL-1β), interleukin-2, interleukin-6, interleukin-16, interleukin-17 and
increased level of interleukin-10, Transforming growth factor beta (TGF-β).
β-sitosterol-SLN significantly (p < .001) reduced the
level of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), vascular
Endothelial Growth Factor (VEGF) and NF-κB. β-sitosterol-SLN significantly increased the
expression of HO-1,Nrf2 and decreased the expression of NF-κB, RANKL, STAT3. In
conclusion, β-sitosterol SLN showed the antiarthritic effect via suppression of NF-kB and
activation of HO-1/Nrf-2 pathway.
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Affiliation(s)
- Feng Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Orthopedics, Xi'an Fourth Hospital, Xi'an, China
| | - Zhiyu Liu
- Department of Orthopedics, Xi'an Fourth Hospital, Xi'an, China
| | - Xijing He
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhanqi Li
- Department of Orthopedics, Xi'an Fourth Hospital, Xi'an, China
| | - Bin Shi
- Department of Orthopedics, Xi'an Fourth Hospital, Xi'an, China
| | - Fengmei Cai
- Department of Pathology, Xi'an Fourth Hospital, Xi'an, China
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3
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Wu G, Nie W, Wang Q, Hao Y, Gong S, Zheng Y, Lv H. Umbelliferone Ameliorates Complete Freund Adjuvant-Induced Arthritis via Reduction of NF-κB Signaling Pathway in Osteoclast Differentiation. Inflammation 2021; 44:1315-1329. [PMID: 33484396 DOI: 10.1007/s10753-021-01418-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/19/2020] [Accepted: 01/08/2021] [Indexed: 12/22/2022]
Abstract
Osteoclasts, bone-resorbing somatic cells, are directly responsible for bone destruction during rheumatoid arthritis. Complete Freund adjuvant (CFA) is a widely used animal model using rodents for studying rheumatoid arthritis (RA), which effectively manifests serious cartilage destruction and progressive bone erosion, affecting synovial joints and serious joint dysfunction. It was considered that joint injury in RA is induced through systemic inflammation pathway. Umbelliferone (UF), a coumarin derivative of Agele marmilosa, possesses anti-inflammatory activity. In the current study, we scrutinize the effect of umbelliferone on CFA-induced arthritis model and explore the possible mechanism on bone destruction. Intradermal administration of CFA (0.05 mL) was to induce RA manifestations in the experimental rats and the same oral administration of UF was received. The anti-arthritic activity of UF was determined by its inhibitory activity on various biochemical markers, viz., pro-inflammatory, inflammatory, antioxidant enzymes, and hematological parameters elevated during RA condition. We also estimated the mRNA expression of osteoclast parameters. Obtained result disclosed significant reduction in the paw edema and increment of the body weight after UF administration. UF reduce the inflammatory mediatory such as COX-2, PGE2, NF-kB, and VEGF; pro-inflammatory cytokines include TNF-α, IL-1β, IL-6, IL-10, and IL-17 significantly. Moreover, UF treatment significantly reduced the osteoclast number via modulating the RANKL/RANK/OPG ratio. Furthermore, administration of umbelliferone significantly (P < 0.001) suppressed the NF-κB and VEGF. Collectively, our results indicated the novel role of umbelliferone in osteoclastogenesis and proved that umbelliferone is a modern therapeutic tool as a natural agent for treating arthritis and other autoimmune disorders with bone degradation.
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Affiliation(s)
- Guofeng Wu
- Department of Articular Orthopaedics, The First People's Hospital of Changzhou, Changzhou, 213000, Jiangsu, China
| | - Wenbo Nie
- Department of Orthopaedics, Shanxian Central Hospital, Heze, 274300, Shandong, China
| | - Qiu Wang
- Department of Surgery, Hot Spring Sanatorium of Linyi, Shandong Coal (Linyi Hedong Central Hospital, Linyi, 276032, Shandong, China
| | - Youguo Hao
- Department of Rehabilitation, Shanghai Putuo People's Hospital, Shanghai, 200060, China
| | - Shaohua Gong
- Department of Spinal surgery, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201999, China
| | - Yuxin Zheng
- Department of Orthopedics, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China
| | - Hao Lv
- Department of Orthopedics Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
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4
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Du Y, Lu C, Morgan RL, Stinson WA, Campbell PL, Cealey E, Fu W, Lepore NJ, Hervoso JL, Cui H, Urquhart AG, Lawton JN, Chung KC, Fox DA, Amin MA. Angiogenic and Arthritogenic Properties of the Soluble Form of CD13. THE JOURNAL OF IMMUNOLOGY 2019; 203:360-369. [PMID: 31189572 DOI: 10.4049/jimmunol.1801276] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 05/15/2019] [Indexed: 11/19/2022]
Abstract
Aminopeptidase N/CD13 is expressed by fibroblast-like synoviocytes (FLS) and monocytes (MNs) in inflamed human synovial tissue (ST). This study examined the role of soluble CD13 (sCD13) in angiogenesis, MN migration, phosphorylation of signaling molecules, and induction of arthritis. The contribution of sCD13 was examined in angiogenesis and MN migration using sCD13 and CD13-depleted rheumatoid arthritis (RA) synovial fluids (SFs). An enzymatically inactive mutant CD13 and intact wild-type (WT) CD13 were used to determine whether its enzymatic activity contributes to the arthritis-related functions. CD13-induced phosphorylation of signaling molecules was determined by Western blotting. The effect of sCD13 on cytokine secretion from RA ST and RA FLS was evaluated. sCD13 was injected into C57BL/6 mouse knees to assess its arthritogenicity. sCD13 induced angiogenesis and was a potent chemoattractant for MNs and U937 cells. Inhibitors of Erk1/2, Src, NF-κB, Jnk, and pertussis toxin, a G protein-coupled receptor inhibitor, decreased sCD13-stimulated chemotaxis. CD13-depleted RA SF induced significantly less MN migration than sham-depleted SF, and addition of mutant or WT CD13 to CD13-depleted RA SF equally restored MN migration. sCD13 and recombinant WT or mutant CD13 had similar effects on signaling molecule phosphorylation, indicating that the enzymatic activity of CD13 had no role in these functions. CD13 increased the expression of proinflammatory cytokines by RA FLS, and a CD13 neutralizing Ab inhibited cytokine secretion from RA ST organ culture. Mouse knee joints injected with CD13 exhibited increased circumference and proinflammatory mediator expression. These data support the concept that sCD13 plays a pivotal role in RA and acute inflammatory arthritis.
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Affiliation(s)
- Yuxuan Du
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109.,Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.,National Center for Clinical Laboratories/Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, National Center of Gerontology, Beijing 100730, China
| | - Chenyang Lu
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Rachel L Morgan
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - William A Stinson
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Phillip L Campbell
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Ellen Cealey
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Wenyi Fu
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109.,Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, China; and
| | - Nicholas J Lepore
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Jonatan L Hervoso
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Huadong Cui
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109.,Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, China; and
| | - Andrew G Urquhart
- Department of Orthopaedic Surgery, University of Michigan Health System, A. Alfred Taubman Health Care Center, Ann Arbor, MI 48109
| | - Jeffrey N Lawton
- Department of Orthopaedic Surgery, University of Michigan Health System, A. Alfred Taubman Health Care Center, Ann Arbor, MI 48109
| | - Kevin C Chung
- Department of Orthopaedic Surgery, University of Michigan Health System, A. Alfred Taubman Health Care Center, Ann Arbor, MI 48109
| | - David A Fox
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109;
| | - Mohammad A Amin
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109
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Kamel KM, Gad AM, Mansour SM, Safar MM, Fawzy HM. Novel Anti-arthritic Mechanisms of Polydatin in Complete Freund's Adjuvant-Induced Arthritis in Rats: Involvement of IL-6, STAT-3, IL-17, and NF-кB. Inflammation 2018; 41:1974-1986. [PMID: 29982962 DOI: 10.1007/s10753-018-0841-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Articular manifestations are the main hall mark for rheumatoid arthritis; inflammation and oxidative stress are involved in its pathogenesis. This study was designed to figure out the possible therapeutic potential of polydatin on experimentally induced arthritis in rats. Polydatin (POLY) was administered (200 mg/kg, p.o.) for 21 days to complete Freund's adjuvant (CFA; 0.1 ml, s.c.)-induced arthritic rats. Meanwhile, methotrexate (MTX; 0.75 mg/kg, i.p.) was given as a reference standard disease-modifying anti-rheumatic drug (DMARD). Both POLY and MTX significantly attenuated articular damage associated with CFA-induced arthritis. This was manifested by reducing levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and matrix metalloproteinase-3 (MMP-3), paralleled with marked decrease in hind paw and ankle diameters. Moreover, POLY and MTX downregulated gene expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) as well as signal transducer and activator of transcription-3 (STAT3) besides hampering immunohistochemical staining of vascular endothelial growth factor (VEGF) and nuclear factor kappa-B (NF-κB). Furthermore, substantial decline in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level associated with significant rise in reduced glutathione content (GSH) was observed. These findings provide an innovative therapeutic approach of POLY as a natural anti-arthritic drug through modulating IL-6/STAT-3/IL-17/NF-кB cascade. Graphical Abstract ᅟ.
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Affiliation(s)
- Kamel M Kamel
- Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt.
| | - Amany M Gad
- Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt
| | - Suzan M Mansour
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
- Pharmacology, Toxicology & Biochemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, End of 90th St., Fifth Settlement, New Cairo, Egypt
| | - Marwa M Safar
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
- Pharmacology & Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Suez Desert Road, El Sherouk City, Cairo, 11837, Egypt
| | - Hala M Fawzy
- Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt
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6
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Kamel KM, Gad AM, Mansour SM, Safar MM, Fawzy HM. Novel Anti-arthritic Mechanisms of Polydatin in Complete Freund’s Adjuvant-Induced Arthritis in Rats: Involvement of IL-6, STAT-3, IL-17, and NF-кB. Inflammation 2018. [DOI: https://doi.org/10.1007/s10753-018-0841-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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7
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Cantatore FP, Maruotti N, Corrado A, Ribatti D. Anti-angiogenic effects of biotechnological therapies in rheumatic diseases. Biologics 2017; 11:123-128. [PMID: 29276377 PMCID: PMC5733924 DOI: 10.2147/btt.s143674] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Introduction Angiogenesis plays a key role in the pathogenesis of numerous rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and vasculitides. Therefore, the inhibition of pathological angiogenesis may be considered a useful therapeutical approach in these rheumatic diseases. Methods This review article is based on a literature research about the role of biotechnological therapies in angiogenesis inhibition. Results and conclusions Several evidences have demonstrated a role for biotechnological therapies in angiogenesis inhibition. Nevertheless, further research and clinical trials are needed to better quantify the real impact of biotechnological therapies on pathological angiogenesis.
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Affiliation(s)
- Francesco Paolo Cantatore
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, Foggia
| | - Nicola Maruotti
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, Foggia
| | - Addolorata Corrado
- Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, Foggia
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School.,National Cancer Institute "Giovanni Paolo II", Bari, Italy
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8
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Amin MA, Campbell PL, Ruth JH, Isozaki T, Rabquer BJ, Alex Stinson W, O'Brien M, Edhayan G, Ohara RA, Vargo J, Domino SE, Koch AE. A key role for Fut1-regulated angiogenesis and ICAM-1 expression in K/BxN arthritis. Ann Rheum Dis 2015; 74:1459-66. [PMID: 24665114 DOI: 10.1136/annrheumdis-2013-204814] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 02/28/2014] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Angiogenesis contributes to the pathogenesis of rheumatoid arthritis. Fucosyltransferases (Futs) are involved in angiogenesis and tumour growth. Here, we examined the role of Fut1 in angiogenesis and K/BxN serum transfer arthritis. METHODS We examined Fut1 expression in human dermal microvascular endothelial cells (HMVECs) by quantitative PCR. We performed a number of angiogenesis assays to determine the role of Fut1 using HMVECs, Fut1 null (Fut1(-/-)), and wild type (wt) endothelial cells (ECs) and mice. K/BxN serum transfer arthritis was performed to determine the contribution of Fut1-mediated angiogenesis in Fut1(-/-) and wt mice. A static adhesion assay was implemented with RAW264.7 (mouse macrophage cell line) and mouse ECs. Quantitative PCR, immunofluorescence and flow cytometry were performed with Fut1(-/-) and wt ECs for adhesion molecule expression. RESULTS Tumour necrosis factor-α induced Fut1 mRNA and protein expression in HMVECs. HMVECs transfected with Fut1 antisense oligodeoxynucleotide and Fut1(-/-) ECs formed significantly fewer tubes on Matrigel. Fut1(-/-) mice had reduced angiogenesis in Matrigel plug and sponge granuloma angiogenesis assays compared with wt mice. Fut1(-/-) mice were resistant to K/BxN serum transfer arthritis and had decreased angiogenesis and leucocyte ingress into inflamed joints. Adhesion of RAW264.7 cells to wt mouse ECs was significantly reduced when Fut1 was lacking. Fut1(-/-) ECs had decreased intercellular adhesion molecule-1 (ICAM-1) expression at mRNA and protein levels compared with wt ECs. ICAM-1 was also decreased in Fut1(-/-) arthritic ankle cryosections compared with wt ankles. CONCLUSIONS Fut1 plays an important role in regulating angiogenesis and ICAM-1 expression in inflammatory arthritis.
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MESH Headings
- Animals
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/pathology
- Arthritis, Experimental/physiopathology
- Cell Adhesion/physiology
- Cell Line
- Cells, Cultured
- Disease Models, Animal
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Fucosyltransferases/deficiency
- Fucosyltransferases/genetics
- Fucosyltransferases/physiology
- Humans
- Intercellular Adhesion Molecule-1/metabolism
- Macrophages/drug effects
- Macrophages/metabolism
- Macrophages/pathology
- Mice
- Mice, Knockout
- Neovascularization, Pathologic/physiopathology
- RNA, Messenger/metabolism
- Tumor Necrosis Factor-alpha/pharmacology
- Galactoside 2-alpha-L-fucosyltransferase
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Affiliation(s)
- Mohammad A Amin
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Phillip L Campbell
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jeffrey H Ruth
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Takeo Isozaki
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Bradley J Rabquer
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - W Alex Stinson
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Martin O'Brien
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gautam Edhayan
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Ray A Ohara
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jonathon Vargo
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Steven E Domino
- Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Alisa E Koch
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA Veteran's Administration, Ann Arbor, Michigan, USA
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9
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Serum Angiogenesis Markers and Their Correlation with Ultrasound-Detected Synovitis in Juvenile Idiopathic Arthritis. J Immunol Res 2015; 2015:741457. [PMID: 26065004 PMCID: PMC4434192 DOI: 10.1155/2015/741457] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 04/13/2015] [Indexed: 11/21/2022] Open
Abstract
Synovial angiogenesis is considered to be an important early step in the pathogenesis of juvenile idiopathic arthritis (JIA). In this study we assessed levels of angiogenic markers in serum or synovial fluid and their possible relevance to disease activity or degree of ultrasound signs of synovial inflammation and angiogenesis in early JIA. The concentration of vascular endothelial growth factor (VEGF), its soluble receptors 1 and 2 (sVEGF-R1, sVEGF-R2), and angiopoietins 1 and 2 (ANG-1, ANG-2) were evaluated in 43 JIA patients and 23 healthy controls. Synovial angiogenesis was assessed by means of Power-Doppler Ultrasonography (PDUS), according to the fourth-grade vascularity scale. VEGF and its receptors' (sVEGF-R1, sVEGF-R2) serum levels were significantly higher in JIA patients (p = 0.002). We found large variation in serum ANG-1 and ANG-2 levels. The PDUS imaging identified increased synovial microvascular blood flow in 15 (35.7%) examined JIA children. Intensity of joint vascularization correlated with higher serum VEGF and its levels was lowest in grade 0 and highest in grade 3 (p < 0.007 and p < 0.001, resp.). In conclusion, the high correlation between synovial microvascular blood flow, serum angiogenic proteins, and symptoms of synovitis may indicate its important role in pathogenesis of JIA.
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10
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Chou CT. Why is biologic therapy useful in spondyloarthritis? Knowledge from synovial immunopathologic studies of spondyloarthritis. Int J Rheum Dis 2012; 15:507-11. [PMID: 23253232 DOI: 10.1111/1756-185x.12006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The pathogenesis of most rheumatic diseases remains unknown. It is believed that both genetic and environmental factors play a pivotal role in the development of synovial inflammation in rheumatoid arthritis (RA), spondyloarthritis (SpA) and osteoarthritis (OA). In the last two decades, there have been many immunopathologic studies on RA, SpA and OA, and the findings revealed different types of arthritis may also present different pathologic patterns. These included higher vascularity and increased infiltration with CD163 macrophages and neutrophils, but relatively low values for lining cell (LL) hyperplasia in SpA synovium. However, the increased LL hyperplasia, as well as CD1a+ cells and the presence of intracellular citrullinated protein were more prominent in RA than in SpA synovitis. Anti-tumor necrosis factor alpha (anti-TNFα) therapy can significantly reduce synovial LL hyperplasia, vascularity and mononuclear cells infiltration in the majority of RA or SpA patients. This may explain why clinically, arthritis patients can get significant improvement after TNFα blocker treatment.
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Affiliation(s)
- Chung-Tei Chou
- Division of Allergy-Immunology-Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
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Strunk J, Rumbaur C, Albrecht K, Neumann E, Müller-Ladner U. Linking systemic angiogenic factors (VEGF, angiogenin, TIMP-2) and Doppler ultrasound to anti-inflammatory treatment in rheumatoid arthritis. Joint Bone Spine 2012; 80:270-3. [PMID: 23098925 DOI: 10.1016/j.jbspin.2012.09.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 09/11/2012] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To evaluate an association between synovial Doppler flow and serum levels of vascular endothelial growth factor (VEGF), angiogenin and TIMP-2 in patients with rheumatoid arthritis during anti-inflammatory treatment with glucocorticoids and TNF-α inhibitors. METHODS Inflamed wrists of 15 patients with rheumatoid arthritis (RA) were examined by two independent ultrasound investigators prior to and at days 3, 7, 14 and 42 after the initiation of treatment with glucocorticoids in therapy-naïve patients or after the beginning of a therapy with a TNF-α inhibitor in patients with DMARD failure. Quantitative three-dimensional power Doppler ultrasonographic assessment of synovial vascularization was compared at each visit with serum levels of VEGF, angiogenin and TIMP-2. RESULTS In the glucocorticoid group, synovial Doppler signals decreased significantly at day 3 (-44%; P=0.003) in comparison to a delayed decrease in the TNF-α inhibitor group after 6 weeks (-46%; P=0.001). A significant reduction of serum VEGF levels could be determined with a delay of 1 week after the decrease of Doppler activity but no correlation was found between both parameters (rho: P=0.7; r=-0.03). Angiogenin concentrations decreased in the TNF group and increased in the GC group. Levels of TIMP-2 did not change significantly in both groups. CONCLUSION The decrease of serum VEGF levels under treatment with glucocorticoids or TNF-α inhibitors followed the reduction of the intra-articular synovial Doppler flow. This result supports the idea that the reduction of synovial perfusion due to anti-inflammatory treatment is not regulated by systemic VEGF, but that the inflamed joints are the source for circulating VEGF.
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Affiliation(s)
- Johannes Strunk
- Krankenhaus Porz am Rhein, Abteilung für Rheumatologie, Urbacher Weg 19, 51149 Köln, Germany.
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12
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Bai YJ, Jiang DX, An N, Shen HB, Hu YQ. Effects of cold-damp and hot-damp environment on VEGF and IL-1 expression in joint cartilage cells in adjuvant arthritis in rats. J TRADIT CHIN MED 2012; 32:256-60. [PMID: 22876453 DOI: 10.1016/s0254-6272(13)60021-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To study the effects of environmental factors on the degree of injury and expression of vascular endothelial growth factor (VEGF) and interleukin-1 (IL-1) in cartilage cells of the joint in a rat model of adjuvant arthritis (AA). METHODS SD rats aged 10 months were randomly divided into 4 groups that varied by temperature and humidity housing conditions and induction of AA: a control group, a model group, a cold-damp group, and a hot-damp group. All groups except the control group were induced with AA. After 4 w, VEGF and IL-1 expression in cartilage cells of ankle joints of hind limbs were observed. RESULTS Mean area, optical density, and numbers of VEGF- and IL-1-positive cells in the model group, the cold-damp group, and the hot-damp group were significantly higher than that of the control group (all P < 0.05). Optical density and positive cell numbers in the cold-damp group and the hot-damp group were significantly higher than that of the model group (all P < 0.05). Optical density and positive cell numbers in the hot-damp group were significantly higher than that of the cold-damp group. Bone in the hot-damp and cold-damp groups was severely injured. CONCLUSION Environmental factors such as high humidity combined with either high or low temperature increase the severity of damage and expression of VEGF and IL-1 in cartilage cells of joints in rats induced with AA.
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Affiliation(s)
- Yun-Jing Bai
- Rheumatism Department, General Hospital of Beijing Military Region, Beijing 100700, China
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13
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Angiogenic growth factors in rheumatoid arthritis. Rheumatol Int 2011; 33:523-7. [DOI: 10.1007/s00296-011-2210-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Accepted: 10/22/2011] [Indexed: 01/01/2023]
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14
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Kudo Y, Kamisawa T, Anjiki H, Takuma K, Egawa N. Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis. J Zhejiang Univ Sci B 2011; 9:602-9. [PMID: 21661440 DOI: 10.1631/jzus.b0820120] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND/AIMS Pancreatic cancer sometimes occurs during the course of chronic pancreatitis. This study aimed to identify risk factors for developing pancreatic cancer associated with chronic pancreatitis. METHODOLOGY The incidence of pancreatic cancer developing in 218 patients with chronic pancreatitis and clinical features of the chronic pancreatitis patients who developed pancreatic cancer were studied. RESULTS Nine patients developed pancreatic cancer. Average period from the diagnosis of chronic pancreatitis to the diagnosis of pancreatic cancer was 9.6 years. All pancreatic cancers were diagnosed at an advanced stage. Only 2 patients had been followed-up periodically. There were no significant differences between chronic pancreatitis patients who developed pancreatic cancer and those who did not in male/female ratio (3.5 vs. 8), average age on diagnosis (65.0 vs. 56.5), alcoholic/non-alcoholic chronic pancreatitis (1.6 vs. 2.6), smoking habits (62.5% vs. 70.7%), diabetes mellitus (77.8% vs. 54.4%), and continued alcohol drinking (37.5% vs. 53.1%). CONCLUSIONS Over the period examined, 4% of chronic pancreatitis patients developed pancreatic cancer. Sex ratio, onset age, etiology, smoking habits, diabetes mellitus, and continued alcohol drinking were not significant risk factors for developing pancreatic cancer in chronic pancreatitis patients. Periodic follow-up due to the possibility of pancreatic cancer is necessary in chronic pancreatitis patients.
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Affiliation(s)
- Yujin Kudo
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
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15
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Fine-mapping resolves Eae23 into two QTLs and implicates ZEB1 as a candidate gene regulating experimental neuroinflammation in rat. PLoS One 2010; 5:e12716. [PMID: 20856809 PMCID: PMC2939884 DOI: 10.1371/journal.pone.0012716] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Accepted: 08/12/2010] [Indexed: 11/22/2022] Open
Abstract
Background To elucidate mechanisms involved in multiple sclerosis (MS), we studied genetic regulation of experimental autoimmune encephalomyelitis (EAE) in rats, assuming a conservation of pathogenic pathways. In this study, we focused on Eae23, originally identified to regulate EAE in a (LEW.1AV1xPVG.1AV1)F2 cross. Our aim was to determine whether one or more genes within the 67 Mb region regulate EAE and to define candidate risk genes. Methodology/Principal Findings We used high resolution quantitative trait loci (QTL) analysis in the 10th generation (G10) of an advanced intercross line (AIL) to resolve Eae23 into two QTLs that independently regulate EAE, namely Eae23a and Eae23b. We established a congenic strain to validate the effect of this region on disease. PVG alleles in Eae23 resulted in significant protection from EAE and attenuated CNS inflammation/demyelination. Disease amelioration was accompanied with increased levels of Foxp3+ cells in the CNS of the congenic strain compared to DA. We then focused on candidate gene investigation in Eae23b, a 9 Mb region linked to all clinical phenotypes. Affymetrix exon arrays were used to study expression of the genes in Eae23b in the parental strains, where none showed differential expression. However, we found lower expression of exon 4 of ZEB1, which is specific for splice-variant Zfhep1. ZEB1 is an interleukin 2 (IL2) repressor involved in T cell development. The splice-specific variance prompted us to next analyze the expression of ZEB1 and its two splice variants, Zfhep1 and Zfhep2, in both lymph node and spleen. We demonstrated that ZEB1 splice-variants are differentially expressed; severity of EAE and higher IL2 levels were associated with down-regulation of Zfhep1 and up-regulation of Zfhep2. Conclusions/Significance We speculate that the balance between splice-variants of ZEB1 could influence the regulation of EAE. Further functional studies of ZEB1 and the splice-variants may unravel novel pathways contributing to MS pathogenesis and inflammation in general.
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Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of etanercept on serum levels of soluble cell adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular endothelial growth factor in patients with rheumatoid arthritis. Scand J Rheumatol 2009; 38:439-44. [PMID: 19922018 DOI: 10.3109/03009740903079321] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Endothelium and adhesion molecules are engaged in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to analyse the effect of etanercept on the levels of soluble cell adhesion molecules (sCAMs) and vascular endothelial growth factor (VEGF) in patients with active RA. METHODS Patients were receiving 50 mg/week of subcutaneous etanercept and 10-25 mg/week of methotrexate (MTX). Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and VEGF were measured by enzyme-linked immunosorbent assay (ELISA) in 18 RA patients (prior to injection) at 0, 3, 6, 9, and 12 months. RESULTS A decrease in serum levels of sICAM-1 (p<0.001), sVCAM-1 (p<0.01), sE-selectin (p<0.01), and VEGF (p<0.001) was observed in RA patients after 3 months of treatment with etanercept. Six months of therapy with etanercept prolonged the suppression of serum sICAM-1 (p<0.01) and even more remarkably diminished sVCAM-1, sE-selectin, and VEGF (in all cases p<0.001) concentrations as compared to baseline (month 0). Treatment also effectively diminished sICAM-1, sVCAM-1, and VEGF levels at months 9 and 12 (in all cases p<0.001), and less significantly sE-selectin (p<0.05 at month 9 and p<0.01 at month 12). The Disease Activity Score including a 28-joint count (DAS28) measured at 3, 6, 9, and 12 months decreased significantly compared to baseline (in all cases p<0.001). CONCLUSION Our study shows that, besides a rapid suppression of disease activity, serum sCAM and VEGF concentrations are downregulated following anti-tumour necrosis factor alpha (TNFalpha) therapy combined with MTX. Prolonged treatment with etanercept sustained or even more remarkably diminished the sCAM and VEGF serum concentrations.
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Affiliation(s)
- P A Klimiuk
- Department of Rheumatology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland.
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Pan R, Gao XH, Li Y, Xia YF, Dai Y. Anti-arthritic effect of scopoletin, a coumarin compound occurring in Erycibe obtusifolia Benth stems, is associated with decreased angiogenesis in synovium. Fundam Clin Pharmacol 2009; 24:477-90. [PMID: 19845767 DOI: 10.1111/j.1472-8206.2009.00784.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Scopoletin is the main constituent of coumarin found in the stems of Erycibe obtusifolia Benth, a traditional Chinese medicine used in the treatment of rheumatoid arthritis. We have previously demonstrated that scopoletin is able to decrease the serum level of uric acid in hyperuricemic mice induced by potassium oxonate, and attenuate croton oil-induced inflammation. In the present study, we evaluated the anti-arthritic effects of scopoletin in rat adjuvant-induced arthritis by assessing paw swelling, pathology, and synovial angiogenesis. It was found that scopoletin, injected intraperitoneally at doses of 50, 100 mg/kg, reduced both inoculated and non-inoculated paw swelling as well as articular index scores, and elevated the mean body weight of adjuvant-induced arthritic rats. Rats treated with higher dose of scopoletin showed a near-normal histological architecture of the joints and a reduced new blood vessel formation in the synovial tissues. Furthermore, scopoletin downregulated the overexpression of vascular endothelial growth factor, basic fibroblast growth factor and interleukin 6 in the synovial tissues of adjuvant-induced arthritic rats. In conclusion, scopoletin is capable of ameliorating clinical symptoms of rat adjuvant-induced arthritis, by reducing numbers of new blood vessels in the synovium and the production of important endogenous angiogenic inducers. Therefore, this compound may be a potential agent for angiogenesis-related diseases and could serve as a structural base for screening more potent synthetic analogs.
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Affiliation(s)
- Rong Pan
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 1 Shennong Road, Nanjing 210038, Jiangsu Province, China
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Plum SM, Park EJ, Strawn SJ, Moore EG, Sidor CF, Fogler WE. Disease modifying and antiangiogenic activity of 2-methoxyestradiol in a murine model of rheumatoid arthritis. BMC Musculoskelet Disord 2009; 10:46. [PMID: 19409094 PMCID: PMC2687416 DOI: 10.1186/1471-2474-10-46] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2009] [Accepted: 05/01/2009] [Indexed: 11/23/2022] Open
Abstract
Background A critical component of disease progression in rheumatoid arthritis (RA) involves neovascularization associated with pannus formation. 2-methoxyestradiol (2ME2) is a naturally occurring molecule with no known physiologic function, although at pharmacologic concentrations it has antiproliferative and antiangiogenic activities. We investigated the impact of orally administered 2ME2 on the initiation and development of proliferative synovitis using the anti-collagen monoclonal antibodies (CAIA) model. Methods Severe polyarticular arthritis was induced in Balb/c female mice by administration of 2 mg of a monoclonal antibody cocktail intravenously into the tail vein of mice. Twenty-four hours following monoclonal antibody administration, mice were injected with 25 μg of LPS (E. coli strain 0111:B4) via the intraperitoneal route. Treatment with 2ME2 (100, 75, 50, 25, 10, 1 mg/kg, p.o., daily), or vehicle control began 24 hrs following LPS challenge and continued to day 21. Hind limbs were harvested, sectioned and evaluated for DMARD activity and general histopathology by histomorphometric analysis and immunohistochemistry (vWF staining). In a separate study, different dosing regimens of 2ME2 (100 mg/kg; q.d. vs q.w. vs q.w. × 2) were evaluated. The effect of treatment with 2ME2 on gene expression of inflammatory cytokines and angiogenic growth factors in the joint space was evaluated 5 and 14 days after the induction of arthritis. Results Mice treated with 2ME2 beginning 24 hours post anti-collagen monoclonal antibody injection, showed a dose-dependent inhibition in mean arthritic scores. At study termination (day 21), blinded histomorphometric assessments of sectioned hind limbs demonstrated decreases in synovial inflammation, articular cartilage degradation, pannus formation, osteoclast activity and bone resorption. At the maximal efficacious dosing regimen (100 mg/kg/day), administration of 2ME2 resulted in total inhibition of the study parameters and prevented neovascularization into the joint. Examination of gene expression on dissected hind limbs from mice treated for 5 or 14 days with 2ME2 showed inhibition of inflammatory cytokine message for IL-1β, TNF-α, IL-6 and IL-17, as well as the angiogenic cytokines, VEGF and FGF-2. Conclusion These data demonstrate that in the CAIA mouse model of RA, 2ME2 has disease modifying activity that is at least partially attributable to the inhibition of neovascular development. Further, the data suggests new mechanistic points of intervention for 2ME2 in RA, specifically inhibition of inflammatory mediators and osteoclast activity.
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Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, Kishimoto T. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol 2008; 19:12-9. [PMID: 18979150 PMCID: PMC2638601 DOI: 10.1007/s10165-008-0125-1] [Citation(s) in RCA: 169] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Accepted: 08/21/2008] [Indexed: 11/29/2022]
Abstract
We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.
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Affiliation(s)
- Norihiro Nishimoto
- Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
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20
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Jin P, Zhang J, Sumariwalla PF, Ni I, Jorgensen B, Crawford D, Phillips S, Feldmann M, Shepard HM, Paleolog EM. Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis. Arthritis Res Ther 2008; 10:R73. [PMID: 18593464 PMCID: PMC2575619 DOI: 10.1186/ar2447] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2008] [Revised: 06/25/2008] [Accepted: 07/01/2008] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Despite the advent of biological therapies for the treatment of rheumatoid arthritis, there is a compelling need to develop alternative therapeutic targets for nonresponders to existing treatments. Soluble receptors occur naturally in vivo, such as the splice variant of the cell surface receptor for vascular endothelial growth factor (VEGF)--a key regulator of angiogenesis in rheumatoid arthritis. Bioinformatics analyses predict that the majority of human genes undergo alternative splicing, generating proteins--many of which may have regulatory functions. The objective of the present study was to identify alternative splice variants (ASV) from cell surface receptor genes, and to determine whether the novel proteins encoded exert therapeutic activity in an in vivo model of arthritis. METHODS To identify novel splice variants, we performed RT-PCR using an mRNA pool representing major human tissue types and tumors. Novel ASV were identified by alignment of each cloned sequence to its respective genomic sequence in comparison with full-length transcripts. To test whether these ASV have biologic activity, we characterized a subset of them for ligand binding, and for efficacy in an animal model of arthritis. The in vivo study was accomplished using adenoviruses expressing secreted ASV. RESULTS We cloned 60 novel human ASV from 21 genes, encoding cell surface receptors--many of which are known to be important in the regulation of angiogenesis. The ASV were characterized by exon extension, intron retention and alternative exon utilization. Efficient expression and secretion of selected ASV--corresponding to VEGF receptor type 1, VEGF receptor type 2, VEGF receptor type 3, angiopoietin receptor Tie1, Met (receptor for hepatocyte growth factor), colony-stimulating factor 1 receptor, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1, Kit, and RAGE--was demonstrated, together with binding to their cognate ligands. Importantly, ASV derived from VEGF receptor type 1 and Tie1, and to a lesser extent from VEGF receptor type 2 and fibroblast growth factor receptor 1, reduced clinical signs of arthritis in vivo. The reduction was paralleled by decreased joint inflammation and destruction. CONCLUSION The present study shows that unique ASV derived from receptors that play key roles in angiogenesis--namely, VEGF receptor type 1 and, for the first time, Tie1--can markedly reduce arthritis severity. More broadly, our results demonstrate that ASV are a source of novel proteins with therapeutic potential in diseases in which angiogenesis and cellular hyperplasia play a central role, such as rheumatoid arthritis.
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MESH Headings
- Angiopoietin-1/metabolism
- Animals
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/metabolism
- Cells, Cultured
- Disease Models, Animal
- Endothelium, Vascular/cytology
- Endothelium, Vascular/metabolism
- Humans
- Mice
- Mice, Inbred DBA
- Neovascularization, Physiologic/physiology
- Protein Binding/physiology
- Protein Isoforms/metabolism
- Protein Isoforms/therapeutic use
- RNA, Messenger/metabolism
- Receptor Protein-Tyrosine Kinases/metabolism
- Receptor Protein-Tyrosine Kinases/therapeutic use
- Receptor, TIE-1/metabolism
- Receptor, TIE-1/therapeutic use
- Severity of Illness Index
- Umbilical Veins/cytology
- Umbilical Veins/metabolism
- Vascular Endothelial Growth Factor Receptor-1/metabolism
- Vascular Endothelial Growth Factor Receptor-1/therapeutic use
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Affiliation(s)
- Pei Jin
- Receptor BioLogix, Inc., Palo Alto, CA 94303, USA
| | - Juan Zhang
- Receptor BioLogix, Inc., Palo Alto, CA 94303, USA
| | - Percy F Sumariwalla
- Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, UK
| | - Irene Ni
- Receptor BioLogix, Inc., Palo Alto, CA 94303, USA
| | | | - Damian Crawford
- Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, UK
| | | | - Marc Feldmann
- Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, UK
| | | | - Ewa M Paleolog
- Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, London W6 8LH, UK
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Klimiuk PA, Fiedorczyk M, Sierakowski S, Chwiecko J. Soluble cell adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) in patients with early rheumatoid arthritis. Scand J Rheumatol 2007; 36:345-50. [PMID: 17963163 DOI: 10.1080/03009740701406460] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The aim of the study was to analyse serum concentrations of soluble cell adhesion molecules (CAMs) in patients with early rheumatoid arthritis (RA) before and after 6 months of treatment with methotrexate (MTX). METHODS We studied 32 RA patients, untreated with disease-modifying anti-rheumatic drugs (DMARDs) or corticosteroids, with disease duration less than 3 years. Twenty osteoarthritis (OA) patients constituted the control group. The analysis of serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) was based on a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS In comparison with OA patients, higher serum concentrations of sICAM-1 (p<0.01), sVCAM-1 (p<0.01), and sE-selectin (p<0.05) were observed in untreated patients with early RA. Six months of treatment with MTX down-regulated serum concentrations of sICAM-1, sVCAM-1, and sE-selectin (in all cases p<0.001) in the RA patients studied. MTX treatment was also followed by a decrease in the clinical markers of RA activity, such as the number of painful and swollen joints, erythrocyte sedimentation rate (ESR), disease activity score (DAS), and C-reactive protein (CRP) levels. CONCLUSIONS Patients with early RA are characterized by high serum concentrations of sICAM-1, sVCAM-1, and sE-selectin. Therapy with MTX resulted in clinical improvement and diminished serum levels of soluble CAMs in the RA patients studied, confirming the effectiveness of MTX in early stages of the disease.
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Affiliation(s)
- P A Klimiuk
- Department of Rheumatology and Internal Diseases, Medical University of Bialystok, Bialystok, Poland.
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22
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Williams AS, Richards PJ, Thomas E, Carty S, Nowell MA, Goodfellow RM, Dent CM, Williams BD, Jones SA, Topley N. Interferon-gamma protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints. ACTA ACUST UNITED AC 2007; 56:2244-54. [PMID: 17599735 DOI: 10.1002/art.22732] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon-gamma (IFNgamma) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin-1beta [IL-1beta] and tumor necrosis factor alpha [TNFalpha]) in modulating inflammation and arthritis in vitro and in vivo. METHODS Monarticular antigen-induced arthritis (AIA) was initiated in IFNgamma-deficient (IFNgamma(-/-)) mice and age-matched wild-type (IFNgamma(+/+)) mice. Joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFNgamma in regulating IL-1beta- and TNFalpha-driven CXCL8 and CCL2 production was quantified by enzyme-linked immunosorbent assay. RESULTS In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFNgamma. IFNgamma appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast-like synoviocytes, IFNgamma modulated both IL-1beta- and TNFalpha-driven chemokine synthesis, resulting in the down-regulation of CXCL8 production. CONCLUSION IFNgamma exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFNgamma signaling in the treatment of inflammatory arthritides.
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Affiliation(s)
- Anwen S Williams
- Wales College of Medicine, Cardiff University, Heath Park, Cardiff, UK.
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23
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Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S, Ciołkiewicz M. Vascular endothelial growth factor in systemic lupus erythematosus: relationship to disease activity, systemic organ manifestation, and nailfold capillaroscopic abnormalities. Arch Immunol Ther Exp (Warsz) 2007; 55:179-85. [PMID: 17557150 PMCID: PMC2765643 DOI: 10.1007/s00005-007-0017-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2006] [Accepted: 12/28/2006] [Indexed: 11/03/2022]
Abstract
INTRODUCTION The aim of the study was to evaluate whether vascular endothelial growth factor (VEGF) serum level is associated with systemic organ involvement, microvascular changes as determined by nailfold capillaroscopy, and disease activity of systemic lupus erythematosus (SLE). MATERIALS AND METHODS Serum levels of VEGF were determined by an enzyme-linked immunosorbent assay in 47 SLE patients and in 30 healthy controls. Nailfold capillaroscopy was performed in all patients and healthy subjects. RESULTS Morphological changes were observed by nailfold capillaroscopy in 45 of 47 (95.7%) SLE patients. Mild capillary changes were found in 16 (34%), moderate in 21 (44.7%), and severe in 8 (17%) SLE patients. All patients with systemic organ involvement showed severe or moderate changes in nailfold capillaroscopy. In comparison with the control group, a higher serum concentration of VEGF in SLE patients was demonstrated (p<0.05). Furthermore, significant differences in VEGF serum concentration between SLE patients with systemic involvement and controls were found (p<0.01). Comparison between patients with active and inactive SLE according to SLEDAI score showed a significantly higher concentration of VEGF in the sera of patients with active SLE (p<0.01). The SLE patients with severe and moderate changes in nailfold capillaroscopy showed significantly higher VEGF serum levels than SLE patients with mild changes (p<0.05) or healthy controls (p<0.01). Moreover, the VEGF serum level correlated significantly with ESR (r=0.580, p<0.0001) and CRP (r=0.512, p<0.005). CONCLUSIONS Our data suggest that VEGF serum level may be a useful marker of disease activity and internal organ involvement in SLE patients. Abnormalities in nailfold capillaroscopy may reflect the extent of microvascular involvement and are associated with systemic manifestation in SLE.
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Affiliation(s)
- Anna Kuryliszyn-Moskal
- Department of Rheumatology and Internal Diseases, Medical University of Białystok, M. Curie-Sklodowskiej 24a, 15-276, Białystok, Poland.
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Tan GH, Huang FY, Wang H, Huang YH, Lin YY, Li YN. Immunotherapy of hepatoma with a monoclonal antibody against murine endoglin. World J Gastroenterol 2007; 13:2479-83. [PMID: 17552032 PMCID: PMC4146767 DOI: 10.3748/wjg.v13.i17.2479] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the capability of a monoclonal antibody (mAb) against murine endoglin to inhibit tumor angiogenesis and suppression of hepatoma growth in murine models.
METHODS: A monoclonal antibody against murine endoglin was purified by affinity chromatography and passively transfused through tail veins in two murine hepatoma models. Tumor volume and survival time were observed at three-day intervals for 48 d. Microvessels in tumor tissues were detected by immunohistochemistry against CD31, and angiogenesis in vivo was determined by alginate encapsulated assay. In addition, tumor cell apoptosis was detected by TUNEL assay.
RESULTS: Passive immunotherapy with anti-endoglin mAb could effectively suppress tumor growth, and prolonged the survival time of hepatoma-bearing mice. Angiogenesis was apparently inhibited within the tumor tissues, and the vascularization of alginate beads was also reduced in the mice passively transfused with anti-endoglin mAb. In addition, increased apoptotic cells were observed within the tumor tissues from the mice passively transfused with anti-endoglin mAb.
CONCLUSION: Passive immunotherapy with anti-endoglin mAb effectively inhibits tumor growth via inhibiting tumor angiogenesis and increasing tumor cell apoptosis, which may be highly correlated with the blockage of endoglin-related signal pathway induced by anti-endoglin mAb.
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MESH Headings
- Alginates
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/therapeutic use
- Apoptosis/drug effects
- Cell Line, Tumor
- Disease Models, Animal
- Endoglin
- Glucuronic Acid
- Hexuronic Acids
- Immunization, Passive/methods
- Intracellular Signaling Peptides and Proteins/immunology
- Liver Neoplasms, Experimental/blood supply
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/immunology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Nude
- Microspheres
- Neovascularization, Pathologic/drug therapy
- Random Allocation
- Signal Transduction/drug effects
- Survival Rate
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Affiliation(s)
- Guang-Hong Tan
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571101, Hainan Province, China.
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25
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Nadiv O, Beer Y, Goldberg M, Agar G, Loos M, Katz Y. Decreased induction of IL-1β in fibroblast-like synoviocytes: A possible regulatory mechanism maintaining joint homeostasis. Mol Immunol 2007; 44:3147-54. [PMID: 17353049 DOI: 10.1016/j.molimm.2007.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2006] [Revised: 01/28/2007] [Accepted: 02/01/2007] [Indexed: 11/15/2022]
Abstract
The response of fibroblast-like synoviocytes (FLS) to inflammatory stimuli was compared to their, respectively, derived dermal fibroblasts (DF) to determine whether regulatory controls exist within FLS to insure normal joint homeostasis. We further analyzed whether the loss of the normal regulatory controls present within the FLS could predispose to the development of non-rheumatic joint disease (non-RA). Primary fibroblast cell lines were generated from synovial and skin tissue from ten rheumatoid arthritis (RA) and ten non-RA patients. Cell lines were pulse labeled with [(35)S]-methionine and stimulated with TNFalpha or IL-1beta. Protein synthesis of IL-1beta, IL-6 and IL-8 was quantitated following immunoprecipitation. Gene expression was determined by Northern blot analysis. We noted, IL-1beta was minimally detected in FLS under nonstimulated conditions. In response to stimulation with IL-1beta or TNFalpha, production of IL-1beta was found to be 3.5 and 5-fold lower in FLS, respectively, when compared to DF from the same individual. In contrast, the production of IL-6 and IL-8 in FLS upon stimulation was 3-fold and 1.6-fold higher, respectively, than in DF. Furthermore, induced IL-1beta production in FLS, normalized relative to their, respectively, stimulated DF, was 2.5 times higher in non-RA versus RA-derived cells (p=0.032), an effect noted even after several passages of growth. Our data suggest that inductive expression of IL-1beta in FLS is under specific inhibitory control. Increased production of IL-1beta in FLS of susceptible individuals may lead to a higher risk of developing severe joint damage even in the absence of systemic inflammation.
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Affiliation(s)
- Orna Nadiv
- Allergy and Immunology Institute, Assaf-Harofeh Medical Center, Zerifin, Israel
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26
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Al-Haggar M, . MR, . MA, . RAB. Soluble Adhesion Molecules in Juvenile Idiopathic Arthritis: Relation to Activity and Clinical Subtype. JOURNAL OF MEDICAL SCIENCES 2006. [DOI: 10.3923/jms.2006.474.479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Appel H, Kuhne M, Spiekermann S, Köhler D, Zacher J, Stein H, Sieper J, Loddenkemper C. Immunohistochemical analysis of hip arthritis in ankylosing spondylitis: Evaluation of the bone–cartilage interface and subchondral bone marrow. ACTA ACUST UNITED AC 2006; 54:1805-13. [PMID: 16736521 DOI: 10.1002/art.21907] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE Previous histopathologic and magnetic resonance imaging studies suggest that the subchondral bone marrow might be the primary site of inflammation in patients with ankylosing spondylitis (AS) and that this might be reflected by inflammation found in hip joints. The aim of this study was to conduct an immunohistologic assessment of the bone-cartilage interface and subchondral bone marrow in AS patients with hip arthritis. METHODS We collected femoral heads from patients with AS, osteoarthritis (OA), and rheumatoid arthritis (RA) who were undergoing hip replacement. The subchondral bone marrow and bone-cartilage interface were assessed immunohistochemically by evaluating infiltrating T cells, microvessel density, and osteoclasts. Areas of the femoral head surface with and without cartilage were assessed separately. RESULTS At sites with surface cartilage, we found subchondral infiltration of CD3+ T cell aggregates at significantly higher numbers in AS patients as compared with OA patients, but not RA patients. At sites of complete cartilage destruction, the frequency of CD3+ T cell aggregates was significantly reduced as compared with sites with cartilage on the surface in AS patients, but not in RA patients. Similar differences were found for CD4+ and CD8+ T cells. Only at sites with surface cartilage, but not those without, angiogenesis and osteoclastic foci in the subchondral bone marrow in AS patients were significantly increased as compared with RA patients and with OA patients. CONCLUSION These findings suggest that the subchondral bone marrow and bone-cartilage interface are primary sites of inflammation in AS and that cartilage might be necessary for the induction of inflammation.
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Affiliation(s)
- Heiner Appel
- Charité Berlin, Campus Benjamin Franklin, Berlin, Germany
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28
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Kiris A, Ozgocmen S, Kocakoc E, Ardicoglu O. Power Doppler assessment of overall disease activity in patients with rheumatoid arthritis. JOURNAL OF CLINICAL ULTRASOUND : JCU 2006; 34:5-11. [PMID: 16353227 DOI: 10.1002/jcu.20175] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
PURPOSE To examine synovial vascularity and flow patterns in hand and wrist joints--metacarpophalangeal (MCP) joints and ulnar stiloid (USTL) regions--of patients with rheumatoid arthritis (RA) using power Doppler sonography (PDUS) and spectral Doppler analysis and to assess the accuracy of PDUS in detecting overall disease activity in RA patients. METHODS Two hundred forty MCP joints and 48 USTL regions in 24 RA patients were examined. Patients were categorized into 2 groups--active and inactive--according to the American College of Rheumatology remission criteria. Resistance indexes (RIs) were measured. RESULTS Flow signals were detected in 50 MCP joints (in 13 patients) and 24 USTL regions (in 16 patients) and spectral analysis was performed in 46 MCP joints (12 patients) and 23 USTL regions (16 patients). The sensitivity and specificity of PDUS in detecting disease activity in RA were 92% and 40%, respectively. There was a negative correlation between flow signal number and RI, with higher scores of flow signals corresponding to lower RIs. CONCLUSION PDUS appears to be a reliable method for assessing inflammatory activity in rheumatoid synovium.
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Affiliation(s)
- Adem Kiris
- Department of Radiology, Firat University, Faculty of Medicine, Elazig, Turkey
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29
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Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S, Ciolkiewicz M. A study on vascular endothelial growth factor and endothelin-1 in patients with extra-articular involvement of rheumatoid arthritis. Clin Rheumatol 2005; 25:314-9. [PMID: 16247585 DOI: 10.1007/s10067-005-0007-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2004] [Revised: 05/03/2005] [Accepted: 05/03/2005] [Indexed: 11/28/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with a wide range of extra-articular manifestations. Recent studies emphasise a key inflammatory role of the endothelial cells, either by overexpression of inflammatory mediators or by the proliferation of new blood vessels, in the disease process leading to the systemic organ involvement. To evaluate the relationship between internal organ manifestations and immunological markers of endothelial activation, serum levels of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 64 RA patients and in 32 healthy controls. In comparison with a control group, higher serum concentrations of VEGF and ET-1 (p<0.001) in RA patients were demonstrated. A comparison between both RA groups with (20 patients) and without systemic involvement (44 patients) showed significantly higher concentrations of VEGF (p<0.05) and ET-1 (p<0.01) in the sera of patients with systemic manifestation. Moreover, a significant positive correlation between VEGF and ET-1 (r=0.475, p<0.001) in RA patients was found. A positive correlation between VEGF and Disease Activity Score (DAS) 28 index (r=0.39, p<0.005) as well as erythrocyte sedimentation rate (ESR) (r=0.564, p<0.0001) and C-reactive protein was found. ET-1 serum level correlated significantly with ESR (r=0.326, p<0.05) and DAS 28 index (r=0.307, p<0.05). These results suggest that the elevated serum levels of VEGF and ET-1 are associated with systemic organ involvement in RA patients and may play a key role in the pathogenesis of extra-articular manifestation of the disease.
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Affiliation(s)
- Anna Kuryliszyn-Moskal
- Department of Rheumatology and Internal Diseases, Medical University of Bialystok, MC Sklodowskiej 24a, 15-276 Bialystok, Poland.
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30
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Strunk J, Bundke E, Lange U. Anti-TNF-α antibody Infliximab and glucocorticoids reduce serum vascular endothelial growth factor levels in patients with rheumatoid arthritis: a pilot study. Rheumatol Int 2005; 26:252-6. [PMID: 15999273 DOI: 10.1007/s00296-005-0619-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2004] [Accepted: 03/05/2005] [Indexed: 10/25/2022]
Abstract
UNLABELLED To compare the effect of oral glucocorticoid (GC) therapy with the effect of intravenous anti-TNF-alpha-therapy on serum VEGF levels of patients with rheumatoid arthritis (RA). Five RA patients (5/8) who had no prior treatment with DMARDs (Disease modifying antirheumatic drugs) or GCs were administered 20 mg prednisolone daily. Three patients who failed more than one DMARD therapy received infusion with Infliximab (200 mg). VEGF-serum levels were measured by enzyme-linked immunosorbent assay before treatment,and at day 10 or 13 during prednisolone therapy, or 14 days after the first Infliximab infusion. Serum VEGF levels in therapy naive RA patients (GC group) were higher than those in pretreated patients who received Infliximab (median serum VEGF level: 1106 vs 320 pg/ml; P=0.1). Treatment with Infliximab as well as GCs significantly decreased serum VEGF levels after 10-14 days in RA patients (median serum VEGF level after treatment: GC group 559 pg/ml, Infliximab group 92 pg/ml; P=0.01 vs without treatment or preinfusion). CONCLUSIONS Anti-TNF-alpha antibody Infliximab as well as GC are able to decrease serum VEGF levels in patients with active RA. Whether therapeutic reduction of serum VEGF levels is associated with inhibition of angiogenesis should be evaluated in future by imaging of synovial vasculature.
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Affiliation(s)
- Johannes Strunk
- Department of Rheumatology, Kerckhoff-Clinic and Foundation, University of Giessen, Benekestrasse 2-8, 61231 Bad Nauheim, Germany.
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31
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Kusabe T, Waguri-Nagaya Y, Tanikawa T, Aoyama M, Fukuoka M, Kobayashi M, Otsuka T, Asai K. The inhibitory effect of disease-modifying anti-rheumatic drugs and steroids on gliostatin/platelet-derived endothelial cell growth factor production in human fibroblast-like synoviocytes. Rheumatol Int 2005; 25:625-30. [PMID: 15990992 DOI: 10.1007/s00296-005-0624-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2004] [Accepted: 03/23/2005] [Indexed: 12/12/2022]
Abstract
Gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) is known to have both angiogenic and arthritogenic activities. The purpose of this study was to investigate whether disease-modifying anti-rheumatic drugs (DMARDs) and steroids are involved in the regulation of GLS expression. Fibroblast-like synoviocytes (FLSs) obtained from patients with rheumatoid arthritis (RA) were cultured and stimulated by interleukin (IL)-1beta with or without DMARDs and steroids. The expression levels of GLS were determined using the reverse transcription-polymerase chain reaction and an ELISA. In cultured rheumatoid FLSs, the expression of GLS mRNA was significantly increased by stimulation with IL-1beta. By contrast, GLS mRNA levels in IL-1beta-stimulated FLSs were reduced by treatment with aurothioglucose (AuTG) and dexamethasone (DEX). These findings indicate that AuTG and DEX have anti-rheumatic activity, which is mediated via the suppression of GLS production. Neither methotrexate (MTX) nor sulfasalazine (SSZ) had a significant influence on GLS levels in our study.
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Affiliation(s)
- Takuma Kusabe
- Department of Musculoskeletal Medicine, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya , 467-8601, Japan
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Chen Y, Donnelly E, Kobayashi H, Debusk LM, Lin PC. Gene therapy targeting the Tie2 function ameliorates collagen-induced arthritis and protects against bone destruction. ACTA ACUST UNITED AC 2005; 52:1585-94. [PMID: 15880817 DOI: 10.1002/art.21016] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE In a previous study, we demonstrated that Tie2 regulates angiogenesis in arthritis. The current study was performed to determine whether systemic delivery of a soluble Tie2 receptor (ExTek) using an adenoviral vector (AdExTek) as a Tie2 inhibitor affects arthritis development and progression in an animal model. METHODS We used a collagen-induced arthritis (CIA) mouse model to study the outcome of treatment with either AdExTek or a control vector. The onset, incidence, and severity of arthritis were quantified. Immunohistologic analysis of endothelium obtained from the paws was performed. Bone destruction in paws was analyzed using phase-contrast radiography. RESULTS The data showed that systemic delivery of ExTek before disease development significantly inhibited the onset, incidence, and severity of arthritis. When AdExTek was given after disease onset, the severity of disease in mice treated with AdExTek was significantly lower than that in the control group at 35 days postimmunization, which correlated with significantly diminished angiogenesis in mouse paws. Strikingly, AdExTek treatment protected bone from erosion in the CIA model and reduced levels of RANKL. No differences in collagen-specific antibodies were detected between these 2 groups. CONCLUSION We demonstrated that blocking Tie2 receptor activation inhibits angiogenesis and arthritis development and protects against bone destruction in a CIA mouse model. These findings identify Tie2 as a therapeutic target for arthritis treatment and imply that interventions designed to target the Tie2 pathway could be clinically beneficial.
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Affiliation(s)
- Ying Chen
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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33
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Ozgocmen S, Kiris A, Kocakoc E, Ardicoglu O, Kamanli A. Evaluation of metacarpophalangeal joint synovitis in rheumatoid arthritis by power Doppler technique: relationship between synovial vascularization and periarticular bone mineral density. Joint Bone Spine 2005; 71:384-8. [PMID: 15474389 DOI: 10.1016/j.jbspin.2003.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2002] [Accepted: 06/26/2003] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To evaluate intra-articular vascularization and flow patterns of the metacarpophalangeal (MCP) joints in rheumatoid arthritis (RA) patients by using power Doppler technique. The relationship between the flow patterns and the regional bone mineral density (BMD) measurements of MCP joints using dual-energy X-ray absorptiometry (DXA) was also assessed. METHODS Fifteen patients (mean age 48.5 +/- 13.8) with a disease duration of 6.8 +/- 4.9 years were included into the study. Thirty MCP joints of three healthy subjects were also assessed as controls. Clinical activity of MCP joint inflammation was classified according to a modified index for synovitis activity based on joint swelling, warmness and pain. Ultrasonography was performed using LOGIQ 7 unit by means of a 6-13 MHz linear array transducer. Gray-scale US and power Doppler sonography (PDS) examination was performed. Using spectral Doppler the quality of flow was determined and the indices of pulsatility (PI) and resistance (RI) were measured in longitudinal plane. The erosive scores of the MCP joints were determined on the plain hand radiographs using Sharp/van der Heijde method. Hand BMD, MCP BMD and the ratio of MCP BMD to whole hand BMD (rBMD) were measured using a Lunar DPX densitometer. RESULTS Total 150 MCP joints of 15 patients and 30 MCP joints of three healthy controls were examined in both hands. Flow was determined in 31 joints (10 moderately active, 21 active) in eight patients whereas seven patients had no quantifiable flow in MCP joints. MCP joints of healthy controls had no quantifiable flow. Mean PI of these joints were 2.17 +/- 2.37 in moderately active and 2.12 +/- 1.93 in active MCP joints. RI was 0.76 +/- 0.12 in moderately active and 0.75 +/- 0.15 in active MCP joints. There was no significant difference in RI and PI of these active and moderately active MCP joints. There was a significant correlation between erosive scores and PI, RI of total MCP joints (r = 0.40 and r = 0.41, P < 0.05). PI and RI also negatively correlated with rBMD (r = -0.46, P < 0.01 and r = -0.36, P < 0.05, respectively). PIc was 4.07 +/- 3.26 and RIc was 0.88 +/- 0.16 in the neighboring soft tissues which were significantly higher than PI and RI of MCP joints (P < 0.001). CONCLUSION Power Doppler ultrasonography (PDUS) is a useful method demonstrating synovial vascularization and flow patterns and offers new alternatives for monitoring disease activity and measurement of therapeutic response. Flow patterns had intimate correlation with intra-articular bone and cartilage destruction.
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Affiliation(s)
- Salih Ozgocmen
- Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Firat University, Faculty of Medicine, 23119 Elazig, Turkey.
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Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S. Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol 2004; 24:111-6. [PMID: 15349798 DOI: 10.1007/s10067-004-0987-3] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2004] [Accepted: 06/04/2004] [Indexed: 11/29/2022]
Abstract
Systemic sclerosis (SSc) is a chronic, multisystemic, autoimmune disease characterised by vascular changes and varying degrees of fibrosis of the skin and visceral organs. Organ systemic involvement in SSc is associated with an altered function of endothelial cells, perivascular infiltrating mononuclear cells and interstitial fibrosis. To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 31 SSc patients and in 30 healthy controls. In comparison with the control group, higher serum concentrations of sVCAM-1, sE-selectin, VEGF and ET-1 were detected in SSc patients (in all cases p<0.001). Elevated concentrations of sVCAM-1 (p<0.05), sE-selectin (p<0.05), VEGF (p<0.05) and ET-1 (p<0.01) dominated in the serum of SSc patients with organ systemic involvement compared to those without systemic manifestation of the disease. These results suggest that the serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 may reflect the extent of internal organ involvement in SSc patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.
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Affiliation(s)
- Anna Kuryliszyn-Moskal
- Department of Rheumatology and Internal Diseases, Medical University of Bialystok, M.C. Sklodowskiej 24a, 15-276 Bialystok, Poland.
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35
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Affiliation(s)
- A E Koch
- Feinberg School of Medicine, Northwestern University and Veteran's Administration Chicago Healthcare System, Lakeside Division, IL 60611, USA.
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36
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Liu JY, Wei YQ, Yang L, Zhao X, Tian L, Hou JM, Niu T, Liu F, Jiang Y, Hu B, Wu Y, Su JM, Lou YY, He QM, Wen YJ, Yang JL, Kan B, Mao YQ, Luo F, Peng F. Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2. Blood 2003; 102:1815-23. [PMID: 12750177 DOI: 10.1182/blood-2002-12-3772] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The breaking of immune tolerance of "self-antigens" associated with angiogenesis is an attractive approach to cancer therapy by active immunity. We used vascular endothelial growth factor receptor-2 (VEGFR-2) as a model antigen to explore the feasibility of the immunotherapy with a vaccine based on a xenogeneic homologous protein. To test this concept, we prepared a quail homologous VEGFR-2 protein vaccine (qVEGFR) based on quail VEGFR-2. At the same time, a protein vaccine based on the corresponding ligand-binding domain of mouse self-VEGFR-2 (mVEGFR) was also prepared and used as a control. We found that immunotherapy with qVEGFR was effective at protective and therapeutic antitumor immunity in several solid and hematopoietic tumor models in mice. Autoantibodies against mouse VEGFR-2 (Flk-1) were identified by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Anti-VEGFR antibody-producing B cells were detectable by ELISPOT. Endothelial deposition of immunoglobulins developed within tumor. VEGF-mediated endothelial cell proliferation was inhibited in vitro by immunoglobulins from qVEGFR-immunized mice. Antitumor activity was caused by the adoptive transfer of the purified immunoglobulins. Antitumor activity and production of autoantibodies against Flk-1 could be abrogated by the depletion of CD4+ T lymphocytes. Angiogenesis was apparently inhibited within the tumors, and the vascularization of alginate beads was also reduced. No marked toxicity was found in the immunized mice. The observations may provide a vaccine strategy for cancer therapy through the induction of autoimmunity against the growth factor receptor associated with angiogenesis in a cross-reaction with single xenogeneic homologous protein.
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Affiliation(s)
- Ji-Yan Liu
- Key Laboratory of Biotherapy of Human Diseases and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Guo Xue Xiang, No. 37, Chengdu, Sichuan, 610041, The People's Republic of China
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Nakahara H, Song J, Sugimoto M, Hagihara K, Kishimoto T, Yoshizaki K, Nishimoto N. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. ARTHRITIS AND RHEUMATISM 2003; 48:1521-9. [PMID: 12794819 DOI: 10.1002/art.11143] [Citation(s) in RCA: 284] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To investigate whether interleukin-6 (IL-6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). METHODS Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL-6, IL-1beta, and/or tumor necrosis factor alpha (TNFalpha) was measured. The inhibitory effect of anti-IL-6R mAb, recombinant IL-1 receptor antagonist (IL-1Ra), and anti-TNFalpha mAb on VEGF production was also examined. RESULTS Serum VEGF levels in RA patients before anti-IL-6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti-IL-6R mAb normalized serum VEGF levels. In the in vitro study, IL-6 and IL-1beta each induced a slight amount of VEGF production in synovial cells, but TNFalpha did not. Although VEGF-inducing activity of these cytokines was not remarkable when they were added alone, IL-6 acted synergistically with IL-1beta or TNFalpha to induce VEGF production. There was no synergistic effect between IL-1beta and TNFalpha. In the presence of all of these cytokines, anti-IL-6R mAb eliminated the synergistic effect of IL-6, IL-1beta, and TNFalpha, while IL-1Ra or anti-TNFalpha mAb did not. CONCLUSION Anti-IL-6R mAb therapy reduced VEGF production in RA. IL-6 is the pivotal cytokine that induces VEGF production in synergy with IL-1beta or TNFalpha, and this may be the mechanism by which IL-6 blockade effectively suppresses VEGF production in synovial fibroblasts.
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Affiliation(s)
- Hideko Nakahara
- Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Osaka, Japan
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Drouart M, Saas P, Billot M, Cedoz JP, Tiberghien P, Wendling D, Toussirot E. High serum vascular endothelial growth factor correlates with disease activity of spondylarthropathies. Clin Exp Immunol 2003; 132:158-62. [PMID: 12653851 PMCID: PMC1808664 DOI: 10.1046/j.1365-2249.2003.02101.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Angiogenesis is involved in chronic inflammatory joint diseases such as rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The spondylarthropathies (SpA) are characterized by enthesitis and synovitis, in which blood vessels participate. The objective of this study was to investigate serum VEGF levels and their potential associations with disease activity markers for SpA. Sera were collected from 105 patients with SpA (72 with ankylosing spondylitis (AS), four with psoriatic arthritis (PsA), six with reactive arthritis (ReA), eight with enteropathic arthropathy and 15 with undifferentiated SpA), 50 patients with rheumatoid arthritis (RA) and 64 healthy controls. Disease activity in SpA patients was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and laboratory parameters of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein level (CRP)]. Serum VEGF levels were significantly higher in SpA patients (316.4 +/- 215.6 pg/ml) and RA patients (405.2 +/- 366.5) than in controls (217.3 +/- 145.2) (P = 0.003). In SpA patients, serum VEGF levels correlated with disease activity indices (BASDAI: r = 0.22, P = 0.04; ESR: r = 0.3, P = 0.003; and CRP: r = 0.23, P = 0.02). Serum VEGF levels were not associated with presence of extra-articular manifestations or syndesmophytes or with the grade of sacroiliitis. These results suggest that VEGF and therefore angiogenesis may play a role in SpA pathogenesis and may serve as a disease activity marker in SpAs.
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Affiliation(s)
- M Drouart
- Department of Rheumatology, University Hospital Jean Minjoz, Besançon, France
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Sumariwalla PF, Cao Y, Wu HL, Feldmann M, Paleolog EM. The angiogenesis inhibitor protease-activated kringles 1-5 reduces the severity of murine collagen-induced arthritis. Arthritis Res Ther 2003; 5:R32-9. [PMID: 12716451 PMCID: PMC154428 DOI: 10.1186/ar608] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2002] [Revised: 09/27/2002] [Accepted: 10/02/2002] [Indexed: 11/10/2022] Open
Abstract
During rheumatoid arthritis there is enlargement and increased cellularity of the synovial lining of joints, before invasion by the synovium of the underlying cartilage and bone. This increased tissue mass requires a network of blood vessels to supply nutrients and oxygen. Disruption of synovial angiogenesis is thus a desirable aim of antiarthritic therapies. Protease-activated kringles 1-5 (K1-5) is an angiogenesis inhibitor related to angiostatin. In common with angiostatin, K1-5 contains the first four kringle domains of plasminogen, but also encompasses the kringle 5 domain, which confers enhanced antiangiogenic activity when compared with angiostatin. The purpose of the present study was to assess the effect on murine arthritis of K1-5. Arthritis was induced in DBA/1 mice by a single injection of bovine collagen. Treatment with K1-5 was commenced on the day of arthritis onset and continued for 10 days, until the end of the experiment. Daily intraperitoneal administration of K1-5 (2 mg/kg body weight) significantly reduced both paw swelling and clinical score (a composite index of the number of arthritic limbs and the severity of disease). The clinical efficacy of this treatment was reflected by a reduction in joint inflammation and destruction, as assessed histologically. These data suggest that antiangiogenic therapies, which block formation of new blood vessels and hence reduce synovial expansion, might be effective in treating rheumatoid arthritis.
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Affiliation(s)
- Percy F Sumariwalla
- Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
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Klimiuk PA, Sierakowski S, Latosiewicz R, Cylwik JP, Cylwik B, Skowronski J, Chwiecko J. Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann Rheum Dis 2002; 61:804-9. [PMID: 12176805 PMCID: PMC1754213 DOI: 10.1136/ard.61.9.804] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cell adhesion molecules and endothelial growth factors have an important role in the infiltrating of rheumatoid synovium with mononuclear cells, leading to the initiation and progression of the disease. OBJECTIVE To investigate whether the serum profile of soluble adhesion molecules and of vascular endothelial growth factor (VEGF) is associated with the histological appearance of rheumatoid arthritis (RA). METHODS Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and VEGF were assessed by enzyme linked immunosorbent assay (ELISA) in 40 patients with RA and 32 patients with osteoarthritis (OA). RESULTS Histological analysis of synovium specimens distinguished two types of rheumatoid synovitis. Twenty four RA samples presented diffuse infiltrates of mononuclear cells without any further microanatomical organisation, whereas in the remaining 16 samples lymphocytic follicles with germinal centre-like structures were identified. In comparison with patients with OA, constituting a control group, higher serum concentrations of sICAM-1 (p<0.001), sVCAM-1 (p<0.001), sE-selectin (p<0.01), and VEGF (p<0.001) were detected in patients with RA. Raised concentrations of sICAM-1, sVCAM-1, and VEGF dominated in the serum of patients with RA with follicular synovitis compared with those with diffuse synovitis (p<0.01 for all comparisons). The serum concentrations of sICAM-1, sVCAM-1, and VEGF correlated with markers of disease activity such as the erythrocyte sedimentation rate and C reactive protein levels. Furthermore, the clinical data analysed in our study indicated that patients with RA with follicular synovitis tend to have more severe disease. CONCLUSIONS The distinct histological appearances of rheumatoid synovitis associated with different serum profiles of sICAM-1, sVCAM-1, and VEGF reflect varied clinical activity of the disease and confirm RA heterogeneity. Patients with different histological forms of synovitis may respond differently to the treatment regimens.
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Affiliation(s)
- P A Klimiuk
- Department of Rheumatology and Internal Diseases, Medical Academy of Bialystok, Bialystok, Poland.
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41
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Vignola S, Picco P, Falcini F, Sabatini F, Buoncompagni A, Gattorno M. Serum and synovial fluid concentration of vascular endothelial growth factor in juvenile idiopathic arthritides. Rheumatology (Oxford) 2002; 41:691-6. [PMID: 12048298 DOI: 10.1093/rheumatology/41.6.691] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To evaluate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of local joint inflammation in juvenile idiopathic arthritis (JIA). METHODS Sera from 50 patients affected with JIA and 10 age-matched healthy controls were tested with a commercial ELISA for VEGF. Corresponding synovial fluid (SF) concentrations of VEGF and p75 soluble tumour necrosis factor receptor (sTNFR) were evaluated in 20 active JIA patients. RESULTS Serum concentrations of VEGF were significantly higher in patients with active polyarticular disease than in patients with active and inactive oligoarticular disease and healthy controls. In JIA patients, serum concentrations of VEGF displayed a significant correlation with a number of clinical and laboratory parameters of disease activity. VEGF concentrations in SF were significantly higher than those detected in corresponding sera. Moreover, a clear correlation was found between corresponding SF and serum VEGF concentrations. In SF, VEGF showed a strong positive correlation with p75 sTNFR. CONCLUSIONS Concentrations of VEGF in SF in patients with JIA are higher than corresponding serum concentrations, suggesting that this pro-angiogenic factor may have a major role in the outgrowth of hyperplastic pannus and tissue damage at the site of tissue inflammation.
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Affiliation(s)
- S Vignola
- Second Division of Paediatrics (Rheumatology Unit), G. Gaslini Scientific Institute for Children, Genoa, Italy
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42
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Yamashita A, Yonemitsu Y, Okano S, Nakagawa K, Nakashima Y, Irisa T, Iwamoto Y, Nagai Y, Hasegawa M, Sueishi K. Fibroblast growth factor-2 determines severity of joint disease in adjuvant-induced arthritis in rats. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 168:450-7. [PMID: 11751992 DOI: 10.4049/jimmunol.168.1.450] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Rheumatoid arthritis (RA), a systemic inflammatory disease of unknown etiology, mainly affects synovial joints. Although angiogenic growth factors, including fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF), may play a critical role in the development and progression of RA joint disease, little information is now available regarding their exact role in initiation and/or progression of RA. In this study, we show that both polypeptides were up-regulated in the rat joint synovial tissue of an adjuvant-induced model of arthritis (AIA), as well as human subjects with RA. FGF-2 overexpression via Sendai virus-mediated gene transfer significantly worsened clinical symptoms and signs of rat AIA, including hind paw swelling and radiological bone destruction, as well as histological findings based on inflammatory reaction, synovial angiogenesis, pannus formation, and osteocartilaginous destruction, associated with up-regulation of endogenous VEGF. FGF-2 gene transfer to non-AIA joints was without effect. These findings suggested that FGF-2 modulated disease progression, but did not affect initiation. Reverse experiments using anti-FGF-2-neutralizing rabbit IgG attenuated clinical symptoms and histopathological abnormalities of AIA joints. To our knowledge, this is the first report indicating direct in vivo evidence of disease-modulatory effects of FGF-2 in AIA, as probably associated with endogenous VEGF function. FGF-2 may prove to be a possible therapeutic target to treat subjects with RA.
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MESH Headings
- Adjuvants, Immunologic
- Animals
- Ankle Joint/diagnostic imaging
- Antibodies/pharmacology
- Arthritis, Experimental/etiology
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/pathology
- Arthritis, Rheumatoid/etiology
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/pathology
- Disease Progression
- Endothelial Growth Factors/metabolism
- Fibroblast Growth Factor 2/antagonists & inhibitors
- Fibroblast Growth Factor 2/genetics
- Fibroblast Growth Factor 2/physiology
- Gene Transfer Techniques
- Genes, Reporter
- Genetic Vectors
- Humans
- Leukocyte Count
- Lymphokines/metabolism
- Male
- Neovascularization, Pathologic
- Radiography
- Rats
- Rats, Inbred Lew
- Sendai virus/genetics
- Synovial Fluid/metabolism
- Synovial Membrane
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factors
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Affiliation(s)
- Akihisa Yamashita
- Division of Pathophysiological and Experimental Pathology, Department of Pathology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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43
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Ballara S, Taylor PC, Reusch P, Marmé D, Feldmann M, Maini RN, Paleolog EM. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. ARTHRITIS AND RHEUMATISM 2001; 44:2055-64. [PMID: 11592367 DOI: 10.1002/1529-0131(200109)44:9<2055::aid-art355>3.0.co;2-2] [Citation(s) in RCA: 174] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To determine whether elevated levels of the angiogenic cytokine vascular endothelial growth factor (VEGF), detected on presentation to an early arthritis clinic, are associated with the development of chronic and erosive arthritis. METHODS Concentrations of VEGF and its soluble receptor, soluble fms-like tyrosine kinase 1 (sFlt-1), were measured by enzyme-linked immunosorbent assay in serum samples from patients with early (<2 years from onset) arthritic symptoms in the peripheral joints, namely early rheumatoid arthritis (RA), self-limiting arthritis (viral, reactive, and idiopathic inflammatory arthritis), or psoriatic arthritis. In addition, measurements were made in random samples from patients with longstanding (>3 years from symptom onset) RA treated with disease-modifying antirheumatic drugs, from patients with osteoarthritis (OA), and from patients with polyarthralgia without arthritis, as well as from nonarthritic controls. RESULTS Serum VEGF levels at presentation were elevated in patients with inflammatory arthritis (RA, psoriatic, and self-limiting arthritis) as well as in patients with OA, in comparison with nonarthritic controls. Moreover, serum VEGF concentrations were significantly higher in patients with early RA than in patients with self-limiting arthritis. Serum VEGF levels at presentation in patients with early RA correlated significantly with the development of radiographic damage after 1 year. Improvement in the clinical symptoms of RA was associated with a reduction in serum VEGF levels. Serum sFlt-1 levels were raised in patients with early and longstanding RA and in those with self-limiting arthritis, and correlated positively with the serum VEGF concentrations in patients with inflammatory arthritis. CONCLUSION These findings implicate the proangiogenic cytokine VEGF in the persistence of inflammatory arthritis, and support the hypothesis that expansion of the synovial vasculature is important for the development of joint destruction in RA.
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Affiliation(s)
- S Ballara
- Imperial College School of Medicine, London, UK
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44
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Abstract
Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.
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MESH Headings
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antibody Specificity
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/therapy
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/immunology
- Autoimmune Diseases/therapy
- Chemotaxis, Leukocyte
- Clinical Trials, Phase I as Topic
- Clinical Trials, Phase II as Topic
- Clinical Trials, Phase III as Topic
- Combined Modality Therapy
- Cytokines/physiology
- Disease Models, Animal
- Double-Blind Method
- Etanercept
- Humans
- Immunization, Passive
- Immunoglobulin G/immunology
- Immunoglobulin G/therapeutic use
- Immunoglobulin Heavy Chains
- Immunoglobulin gamma-Chains
- Immunosuppressive Agents/therapeutic use
- Infliximab
- Mice
- Multicenter Studies as Topic
- Randomized Controlled Trials as Topic
- Receptors, Tumor Necrosis Factor/immunology
- Receptors, Tumor Necrosis Factor/therapeutic use
- Recombinant Fusion Proteins/immunology
- Recombinant Fusion Proteins/therapeutic use
- Safety
- Treatment Outcome
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/physiology
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Affiliation(s)
- M Feldmann
- Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, United Kingdom.
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45
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Giatromanolaki A, Sivridis E, Athanassou N, Zois E, Thorpe PE, Brekken RA, Gatter KC, Harris AL, Koukourakis IM, Koukourakis MI. The angiogenic pathway "vascular endothelial growth factor/flk-1(KDR)-receptor" in rheumatoid arthritis and osteoarthritis. J Pathol 2001; 194:101-8. [PMID: 11329148 DOI: 10.1002/path.842] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Active angiogenesis, together with an up-regulation of angiogenic factors, is evident in the synovium of both rheumatoid arthritis (RA) and osteoarthritis (OA). The present study assessed, by immunohistochemistry, the microvessel density in the synovium of these arthritides and in normal controls, in relation to the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) and the apoptosis-related proteins bcl-2 and p53. More importantly, using the novel 11B5 MAb, the activated "VEGF/flk-1(KDR)-receptor" microvessel density was assessed. VEGF expression in fibroblasts was diffuse in both RA and OA. Diffuse PD-ECGF expression of fibroblasts was noted in all cases of RA, while fibroblast reactivity was focal in the OA material. The standard microvessel density (sMVD), as assessed with the anti-CD31 monoclonal antibody (MAb), was higher in RA (64+/-12) and in OA (65+/-16) than in normal tissues (52+/-8; p=0.008 and 0.0004, respectively). The activated microvessel density (aMVD), assessed with the 11B5 MAb, was significantly higher in RA (29+/-10) than in OA (17+/-4; p<0.0001) and than in normal tissues (14+/-2; p<0.0001). The "activation ratio" (aMVD/sMVD) was statistically higher in RA (0.46+/-0.17) than in OA and normal synovial tissues, the latter two having a similar ratio (0.28+/-0.08 and 0.26+/-0.03, respectively). Cytoplasmic bcl-2 expression was frequent in the synovial cells of OA, but rare in RA. Nuclear p53 protein accumulation was never observed. It is suggested that the angiogenic pathway VEGF/flk-1(KDR) may play an important role in the pathogenesis of RA and OA. Thus, failure of VEGF/flk-1(KDR) activation, in the presence of increased VEGF expression, may indicate a synovium with an impaired capacity to establish a viable vasculature, consistent with the degenerative nature of OA. On the other hand, the activated angiogenesis in RA shows a functional, still pathologically up-regulated VEGF/flk-1(KDR) pathway. Whether restoration of an impaired VEGF/flk-1(KDR) pathway in OA, or inhibition of this in RA, would prove of therapeutic importance requires further investigation.
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Affiliation(s)
- A Giatromanolaki
- Department of Pathology, Democritus University of Thrace, P.O. Box 12, Alexandroupolis 68100, Greece
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46
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Scola MP, Imagawa T, Boivin GP, Giannini EH, Glass DN, Hirsch R, Grom AA. Expression of angiogenic factors in juvenile rheumatoid arthritis: correlation with revascularization of human synovium engrafted into SCID mice. ARTHRITIS AND RHEUMATISM 2001; 44:794-801. [PMID: 11315918 DOI: 10.1002/1529-0131(200104)44:4<794::aid-anr135>3.0.co;2-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Although increased vascularity was noted in early histopathologic studies of juvenile rheumatoid arthritis (JRA) synovium, the available data on angiogenesis in JRA are very limited. The main purposes of this study were to assess expression of the key angiogenic factors in JRA synovium, and to evaluate a SCID mouse model of JRA as an approach to study in vivo regulation of the expression of these factors in JRA. METHODS RNase protection assay was used to assess the expression of the key angiogenic factors in fresh JRA synovium and in JRA synovial tissue fragments that had been minced and then implanted into SCID mice. Vascularity of the samples was assessed by immunohistochemical staining for von Willebrand factor. Synovial specimens obtained from patients with osteoarthritis (OA) or other noninflammatory arthropathies were used as controls. RESULTS Detectable levels of messenger RNA for vascular endothelial growth factor and angiopoietin 1 and their respective receptors, as well as endoglin and thrombin receptors, were present in all JRA tissue specimens studied. The levels of expression of these factors in JRA tissues were significantly higher than those in tissues obtained from patients with OA or other noninflammatory arthropathies. Furthermore, increased expression of the key angiogenic factors in the fresh JRA tissues correlated with the exuberant revascularization of JRA minced tissue fragments implanted into SCID mice. This was in sharp contrast to the poor revascularization of implanted OA tissues. CONCLUSION JRA synovium is characterized by high angiogenic activity. SCID mouse-human JRA synovium chimeras may provide a good approach to study the in vivo regulation of angiogenesis in JRA.
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MESH Headings
- Angiopoietin-1
- Animals
- Antigens, CD
- Arthritis, Juvenile/immunology
- Arthritis, Juvenile/metabolism
- Disease Models, Animal
- Endoglin
- Endothelial Growth Factors/genetics
- Endothelial Growth Factors/metabolism
- Female
- Humans
- Lymphokines/genetics
- Lymphokines/metabolism
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, SCID
- Neovascularization, Pathologic/metabolism
- Osteoarthritis/metabolism
- RNA, Messenger/metabolism
- Receptors, Cell Surface
- Receptors, Thrombin/genetics
- Receptors, Thrombin/metabolism
- Synovial Membrane/immunology
- Synovial Membrane/metabolism
- Synovial Membrane/transplantation
- Tissue Transplantation
- Transplantation, Heterologous
- Vascular Cell Adhesion Molecule-1/genetics
- Vascular Cell Adhesion Molecule-1/metabolism
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factors
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Affiliation(s)
- M P Scola
- Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA
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47
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Buma P, Groenenberg M, Rijken PF, van den Berg WB, Joosten L, Peters H. Quantitation of the changes in vascularity during arthritis in the knee joint of a mouse with a digital image analysis system. THE ANATOMICAL RECORD 2001; 262:420-8. [PMID: 11275972 DOI: 10.1002/ar.1050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Many joint and bone diseases are caused by, or associated with vascular changes. Particularly in rheumatoid arthritis, vascular sprouting of synovial vessels plays a major role in the generation of joint pathology. To assess the effects of pharmaceuticals that are designed to inhibit neovascularization, we developed a quantitative procedure to measure vascular changes in cross-sections of the mouse knee joint during arthritic inflammation. Arthritis was induced in the knee joint of C57Black6 mice by a single subpatellar injection of methylated BSA after previous immunization. Total vascularity was visualized with a specific monoclonal rat anti-mouse antibody (9F1). Functional vessels were detected with the fluorescent perfusion marker Hoechst 33342. The localization of Hoechst and the vascular marker 9F1 were analyzed in separate images with an automated digital image processing system. By combining the two images, total vascularity and the perfusion status of the vessels during arthritis could be established. The digital image system measures synovial area (SA), number of all blood vessels (NBV) and the number of perfused blood vessels (NpBV). From these parameters the percentage of perfused vessels (perfusion fraction; PF), the vessel density (VD = NBV/SA) and the density of perfused vessels (VDp = NpBV/SA) can be calculated. The measurements showed that the area of synovial tissue had increased during arthritis. Moreover, both the number of blood vessels (NBV) and the number of perfused vessels (NpBV) in the synovial area had increased significantly on Days 4 and 7 after arthritis induction. This procedure enabled quantitation of total vascularity and of functional blood vessels in cross-sections of synovial tissue. It is expected to be a powerful tool, not only to analyze the effects of anti-angiogenic therapies in animal models of arthritis, but could also be applicable to study vascular and perfusion changes in vascular related diseases of the skeleton.
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Affiliation(s)
- P Buma
- Department of Orthopaedics, Orthopaedic Research Laboratory, University Medical Center, Nijmegen, The Netherlands.
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48
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Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, Woodruff DC, Burdick MD, Strieter RM. Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. ARTHRITIS AND RHEUMATISM 2001; 44:31-40. [PMID: 11212173 DOI: 10.1002/1529-0131(200101)44:1<31::aid-anr5>3.0.co;2-4] [Citation(s) in RCA: 109] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Angiogenesis, the growth of new blood vessels, is vital to the ingress of inflammatory leukocytes in rheumatoid arthritis (RA) synovial tissue and to the growth and proliferation of RA pannus. The factors that mediate the growth of new blood vessels have not been completely defined. This study examined the ability of Glu-Leu-Arg (ELR)-containing chemokines to induce angiogenesis in the RA joint. METHODS To reflect angiogenic activity in vivo, we selected a model using whole human synovial tissue rather than isolated cells. Tissues were examined by immunohistochemistry and enzyme-linked immunosorbent assay, and tissue homogenates were immunoneutralized and assayed for their ability to induce endothelial cell chemotaxis and rat corneal neovascularization. RESULTS Cells expressing interleukin-8 (IL-8) and epithelial neutrophil activating peptide 78 (ENA-78) were located in proximity to factor VIII-related antigen-immunopositive endothelial cells. RA homogenates produced more IL-8 and ENA-78 compared with normal synovial tissue homogenates. Moreover, homogenates from RA synovial tissue produced significantly more chemotactic activity for endothelial cells in vitro and angiogenic activity in the rat cornea in vivo than did normal synovial tissue homogenates. The effects of IL-8 and ENA-78 accounted for a significant proportion of the chemotactic activity of endothelial cells and angiogenic activity found in RA synovial tissue homogenates. CONCLUSION These results indicate that the ELR-containing chemokines IL-8 and ENA-78 are important contributors to the angiogenic activity found in the inflamed RA joint. It is possible that efforts aimed at down-regulating these chemokines offer a novel targeted therapy for the treatment of RA.
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Affiliation(s)
- A E Koch
- Northwestern University Medical School and Veterans Administration Chicago Health Care System, Lakeside Division, Illinois, USA
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49
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Walsh DA, Pearson CI. Angiogenesis in the pathogenesis of inflammatory joint and lung diseases. ARTHRITIS RESEARCH 2001; 3:147-53. [PMID: 11299055 PMCID: PMC128891 DOI: 10.1186/ar292] [Citation(s) in RCA: 121] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2000] [Revised: 01/26/2001] [Accepted: 02/08/2001] [Indexed: 12/30/2022]
Abstract
This paper reviews hypotheses about roles of angiogenesis in the pathogenesis of inflammatory disease in two organs, the synovial joint and the lung. Neovascularisation is a fundamental process for growth and tissue repair after injury. Nevertheless, it may contribute to a variety of chronic inflammatory diseases, including rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis. Inflammation can promote angiogenesis, and new vessels may enhance tissue inflammation. Angiogenesis in inflammatory disease may also contribute to tissue growth, disordered tissue perfusion, abnormal ossification, and enhanced responses to normal or pathological stimuli. Angiogenesis inhibitors may reduce inflammation and may also help to restore appropriate tissue structure and function.
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Affiliation(s)
- D A Walsh
- Academic Rheumatology, University of Nottingham Clinical Sciences Building, City Hospital, Nottingham, UK.
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Mason JC, Lidington EA, Yarwood H, Lublin DM, Haskard DO. Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis. ARTHRITIS AND RHEUMATISM 2001; 44:138-50. [PMID: 11212152 DOI: 10.1002/1529-0131(200101)44:1<138::aid-anr18>3.0.co;2-g] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Decay-accelerating factor (DAF) is a widely expressed, multifunctional cell surface protein involved in complement regulation and cell signaling. Previous studies have demonstrated that endothelial cell (EC) DAF is up-regulated by tumor necrosis factor alpha and inhibits complement binding. Because vascular endothelial growth factor (VEGF) is cytoprotective to endothelium and is expressed at sites of chronic inflammation, we hypothesized that VEGF may induce DAF expression during inflammatory angiogenesis. METHODS Human umbilical vein and dermal microvascular EC were isolated using routine procedures, and the regulation and function of DAF, as well as other complement-regulatory proteins (membrane cofactor protein and CD59), were analyzed following stimulation with VEGF. RESULTS Incubation of large- or small-vessel EC with VEGF led to increased expression of DAF, with maximal expression after 48-72 hours of stimulation. This effect depended on the activation of protein kinase C (PKC) and required increased steady-state messenger RNA levels and de novo protein synthesis. Although VEGF-induced EC proliferation was inhibited by both p38 and p42/44 mitogen-activated protein kinase (MAPK) antagonists, DAF up-regulation in response to VEGF was only sensitive to inhibition of p38 MAPK. VEGF-stimulated EC showed a 60% reduction in C3 deposition following complement activation, and this resulted in a marked reduction in complement-mediated EC lysis. These protective effects were abolished by anti-DAF monoclonal antibody 1H4. CONCLUSION This study confirms the importance of PKC for the regulation of DAF expression by EC and reveals VEGF to be a physiologic agonist for this pathway. The up-regulation of DAF expression by VEGF may represent an important mechanism for the protection of EC from complement-mediated injury during angiogenesis in inflammatory rheumatic diseases.
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Affiliation(s)
- J C Mason
- The BHF Cardiovascular Medicine Unit, Imperial College School of Science, Technology, and Medicine, Hammersmith Hospital, London, UK
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