Multicentric Castleman disease (MCD) is

Human parvovirus B19 (B19) DNA was detected in the synovial tissues in 30 of 39 patients with rheumatoid arthritis (RA), and infrequently in those with osteoarthritis and traumatic joints. On the other hand, the expression of the B19 antigen VP-1 was specific (

Monocytes/macrophages (M phi) have been implicated in the pathogenesis of lupus nephritis (LN), but the precise molecular mechanism of recruitment and activation of M phi in LN remains unclear. To clarify the involvement of chemotactic cytokines (chemokines) in those events, we measured levels of monocyte chemotactic and activating factor (MCAF, also termed monocyte chemoattractant protein-1, MCP-1) in urines and sera derived from 42 patients with LN. Both urinary and serum MCAF levels were significantly higher in patients with LN as compared with 22 healthy volunteers (10.3 +/- 3.2 vs. 1.0 +/- 0.1 pg/ml . creatinine, 212.2 +/- 75.8 vs. 66.1 +/- 15.5 pg/ml, respectively, P < 0.05, mean +/- SEM). Histological examination of renal lesions from 41 patients classified 19 as active according to the WHO-defined classes IIIb, IVb and IVc, and 22 as inactive by the WHO-defined classes I, II, IIIc, IVd and V. Urinary MCAF levels in the patients with active lesions were significantly higher than those with inactive lesions (20.3 +/- 6.4 vs. 1.7 +/- 0.3 pg/ml . creatinine, P < 0.01). Moreover, elevated urinary MCAF levels were dramatically decreased during steroid therapy-induced convalescence in 29 patients examined serially (13.9 +/- 4.5 vs. 5.3 +/- 1.7 pg/ml . creatinine, P < 0.001), whereas serum MCAF levels did not change significantly. Endothelial cells, renal epithelial cells and infiltrating mononuclear cells in the tubulointerstitial regions were MCAF-positive in immunohistochemical as well as in situ hybridization analysis. These observations suggest that MCAF is probably involved in the pathogenesis of LN with active lesions, possibly through the recruitment and activation of M phi, and that measurement of urinary MCAF levels may be a useful clinical tool for monitoring the disease activity of LN.

Background-Although it has been demonstrated that matrix metalloproteinases (MMPs) play an important role in the arterial remodeling in atherosclerosis and restenosis, it is not clear which MMP is involved in which process. To define the role of MMP-2 in arterial remodeling, we evaluated the influence of the targeted deletion of the MMP-2 gene on vascular remodeling after flow cessation in the murine carotid arteries. Methods and Results-The left common carotid arteries of wild-type and MMP-2-deficient mice were ligated just proximal to their bifurcations, and the animals were then processed for morphological and biochemical studies at specific time points. MMP-2 activity and mRNA levels increased in ligated carotid arteries of wild-type mice on the basis of observation by gelatin zymography and quantitative real-time RT-PCR. There was significantly less intimal hyperplasia in MMP-2-deficient mice at 2 and 4 weeks after ligation than there in wild-type mice. Arterial explants from the aorta of MMP-2-deficient mice showed that smooth muscle cell (SMC) migration was inhibited in comparison with wild-type mice. The chemoattractant-directed invasion through a reconstituted basement membrane barrier was significantly reduced in cultured SMCs derived from MMP-2-deficient mice, although no difference was observed in SMC migration across the filter or in proliferative response between the control and MMP-2-deficient mice. Conclusions-In

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Objective-Although it has been reported that matrix metalloproteinase (MMP)-2 is a major proteinase in atherosclerotic plaque lesions, there is no direct evidence of the role of MMP-2 in atherosclerotic lesion formation. In the present study we determined the role of MMP-2 in atherosclerosis plaque development using apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Methods and Results-To generate MMP-2-deficient, apoE-deficient mice (MMP-2 Ϫ/Ϫ :apoE Ϫ/Ϫ ), MMP-2 Ϫ/Ϫ mice were crossed with apoE Ϫ/Ϫ mice. After 8 weeks of feeding with a lipid-rich diet, morphological and biochemical studies of the aortic sinus and arch were conducted. A significant reduction of the atherosclerotic plaque in the aortic sinus and arch with the decrease in smooth muscle cell-positive area was observed in MMP-2 Ϫ/Ϫ :apoE Ϫ/Ϫ mice compared with that of MMP-2 ϩ/ϩ :apoE Ϫ/Ϫ mice. Macrophage-and collagen-positive areas were less in aortic sinus but not in aortic arch in MMP-2 Ϫ/Ϫ :apoE Ϫ/Ϫ mice. There was no difference of MMP-9 mRNA expression in the plaque lesion between the 2 genotypes. A much lower level of mRNA expression of TIMP-1 and TIMP-2 was detected in the atherosclerotic plaque lesions of MMP-2 Ϫ/Ϫ :apoE Ϫ/Ϫ mice than in those of MMP-2 ϩ/ϩ :apoE Ϫ/Ϫ mice. Key Words: atherosclerosis Ⅲ collagen Ⅲ metalloproteinases Ⅲ plaque I n human or animal models of atherosclerosis, varying matrix metalloproteinases (MMPs) have been demonstrated to increase in atherosclerotic lesions, including MMP-1, -2, -3, -7, -9, -12, -13, and MT-MMPs. 1-3 MMPs have been believed to contribute to the development and progression of atherosclerosis. 1-3 However, there are only limited data providing direct evidence of the contribution of MMPs to the development of atherosclerotic lesions. Although MMP activity is commonly considered instrumental to the development of atherosclerotic lesions, this notion has been challenged by recent studies in gene-targeting mice. It has been reported that overexpression of the tissue inhibitor of metalloproteinases-1 (TIMP-1) reduced atherosclerotic lesions in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. 4 The deletion of the TIMP-1 gene resulted in either a reduction of or no change in the plaque size in the apoE Ϫ/Ϫ mice. 5,6 Atherosclerotic lesions were significantly larger in mice with a combined deficiency of apoE and MMP-3 than in apoE Ϫ/Ϫ mice. 7 Overexpression of MMP-1 in apoE Ϫ/Ϫ mice, which is not normally expressed in mice, decreased the extent of atherosclerosis. 8 A more recent study demonstrated that MMP-9 deficiency but not MMP-12 deficiency reduced the atherosclerotic lesion growth in apoE Ϫ/Ϫ mice. 9 MMP-13 deficiency had no effect on atherosclerotic plaque formation with similar accumulation of plaque macrophages and smooth muscle cells, but contained more interstitial collagen in apoE Ϫ/Ϫ mice. 10 These results seemingly contradict a central tenet in our understanding of atherosclerosis-that increased MMP activity leads to the formation of a thicker neointima-suggesting that the role of individual MMPs in pla...

Abstract-Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2 ϩ/ϩ and MMP-2 Ϫ/Ϫ mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in MMP-2 Ϫ/Ϫ young and old mice remained impaired throughout the follow-up period. At day 35, microangiography and anti-L-lectin immunohistochemical staining revealed lesser developed collateral vessels and capillary formation in both old and young MMP-2 Ϫ/Ϫ mice compared with the age-matched MMP-2 ϩ/ϩ mice. An aortic-ring culture assay showed a markedly impaired angiogenic response in MMP-2 Ϫ/Ϫ mice, which was partially recovered by supplementation of the culture medium with recombinant MMP-2. Aorta-derived endothelial cells or bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit ϩ cells from MMP-2 Ϫ/Ϫ showed marked impairment of invasive or/and proliferative abilities. At day 7, plasma and ischemic tissues of vascular endothelial growth factor protein were reduced in MMP-2 Ϫ/Ϫ . Flow cytometry showed that the numbers of EPC-like CD31 ϩ c-Kit ϩ cells in peripheral blood markedly decreased in MMP-2-deficient mice. Transplantation of bone marrow-derived mononuclear cells from MMP-2 ϩ/ϩ mice restored neovascularization in MMP-2 Ϫ/Ϫ young mice. These data suggest that MMP-2 deficiency impairs ischemia-induced neovascularization through a reduction of endothelial cell and EPC invasive and/or proliferative activities and EPC mobilization. (Circ Res. 2007;100:904-913.) Key Words: ischemia Ⅲ angiogenesis Ⅲ matrix metalloproteinase Ⅲ endothelium Ⅲ mobilization Ⅲ migration I t is well known that the process of new blood vessel formation is associated with extracellular matrix (ECM) remodeling involving various proteolytic systems. Among such systems, matrix metalloproteinases (MMPs) are a family of zincdependent endopeptidases comprising at least 20 members that are collectively capable of degrading all known ECM components. 1,2 A number of studies have shown that various kinds of MMPs were upregulated in ischemia-induced angiogenesis. 3 Although MMP activity is commonly thought to be involved in the process of angiogenesis, this notion has been challenged by recent studies using genetic or biological target methods. It has been reported that MMP-9 deficiency reduced neovascularization and tumor growth. 4 Study of membrane-type1 (MT1)-MMP knockout mice revealed that the deficiency impaired neovascularization in a mouse corneal micropocket model. 5 Whereas MMP-1 and MMP-10 appear to control the process of vascular regression rather than morphogenesis. 6 On the other hand, certain MMPs, including MMP-12 and MMP-7, are capable of converting plasminogen into angiostatin to inhibit endothelial cell (EC) tubulogenesis in vitro. 7 Interestingly, it has been reported that tiss...

Human parvovirus B19 (B19) infects human erythroid cells expressing P antigen. However, some cell lines that were positive for P antigen failed to bind B19, whereas some cell lines had an ability to bind B19 despite undetectable expression of P antigen. We here demonstrate that B19 specifically binds with Ku80 autoantigen on the cell surface. IntroductionHuman parvovirus B19 (B19) infects erythroid-lineage cells through P antigen and causes various clinical symptoms such as erythema infectiosum, anemia, polyarthritis, or fetal hydrops in humans. 1,2 The cellular receptor for B19 infection has been regarded as blood group P antigen based on the failure of B19 infection in a patient with an hereditary defect of P antigen. 3 However, the target cells of B19 may be not be exclusively P-antigen-positive erythroidlineage cells, as illustrated by the poor relationship between P antigen expression levels and the efficiency of B19 infection 4 or the failure of B19 binding to globoside. 5 Recently, Weigel-Kelley et al described the role of ␣5␤1 integrin as the cellular coreceptor for B19 infection. 6 The notion that B19 receptor is not solely P antigen may be compatible with clinical findings that B19 has been detected in mononuclear cells of blood or tonsils with acute or prolonged B19 infection. 7,8 Also, following B19 infection, the numbers of peripheral blood lymphocytes may decrease despite undetectable levels of P antigen on their cell surface. 9,10 Finally, autoimmune-like phenomena including antinuclear antibodies, rheumatoid factors, or antiphospholipid antibodies are often associated with B19 infection, 8,11 and the levels of tumor necrosis factor ␣ (TNF-␣) and interferon ␥ (IFN-␥) secreted from macrophages or T cells are elevated during acute or prolonged B19 infection. 12 Clinical studies have shown that B19 DNA can be amplified from joint samples by polymerase chain reaction (PCR), 13,14 and infective B19 was detected in the articular lesions of patients with rheumatoid arthritis. B19 transcripts and B19 protein viral protein 1 (VP1) were also present in T cells, B cells, macrophages, and follicular dendritic cells. 14 The cellular mechanism that may allow B19 binding and its entry into nonerythroid cells has not been elucidated. In the present study, we explored a putative receptor for B19 that was distinct from P antigen. Materials and methods CellsMacrophage cell lines U937, urinary bladder carcinoma cell line T24, colon cancer cell line SW620, renal adenocarcinoma cell line ACHN, and HeLa cells were provided by the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan). Human erythroid cell line KU812Ep6 15 was provided by E. Miyagawa (Institute of Fuji Rebio, Tokyo, Japan). T-cell line H9 was purchased from American Type Culture Collection (Manassas, VA). Bone marrow samples were obtained from the volunteers who gave informed consent for the use of their samples for our study. Informed consent was provided in accordance with the Declar...