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      Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

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          Background: Latent transforming growth factor-β-binding protein 1 (LTBP-1) and fibrillin-1 were shown to colocalize and interact in the extracellular matrix of the skin and vasculature. This interaction may regulate transforming growth factor-β (TGF-β) activity. TGF-β is an important progression factor for glomerular diseases. We hypothesized that LTBP-1 and fibrillin-1 are coexpressed in the glomerulus and upregulated during glomerulonephritis. Methods: Acute anti-Thy1.1 glomerulonephritis was induced with a single intravenous injection (1 mg/kg body weight) of a monoclonal anti-Thy1.1 antibody in rats. Real-time RT-PCR and immunohistochemical analyses for LTBP-1 and fibrillin-1 were performed. Results: Induction of glomerular LTBP-1 mRNA was detected on day 2 of disease, while mRNA for fibrillin-1 was already upregulated 1 day after induction of disease. Both LTBP-1 and fibrillin-1 showed a mesangial distribution. An expansion of the LTBP-1 and fibrillin-1-positive mesangial area was seen on day 6 of disease, when transient matrix accumulation was most prominent. On day 12 of disease, glomerular LTBP-1 and fibrillin-1 immunoreactivities had returned to control levels. In serial sections, some colocalization of LTBP-1 and fibrillin-1 was detected in control as well as in nephritic glomeruli. Conclusion: Mesangial expression of LTBP-1 and fibrillin-1 is induced early in experimental nephritis and LTBP-1 and fibrillin-1 are partially colocalized in the nephritic glomerulus. An interaction of these molecules could stabilize latent TGF-β complexes and thus attenuate the activation of TGF-β during this self-limited glomerular disease.

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          TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome

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            Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein

            The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calvarial cells, which form mineralized bonelike nodules, both LTBP and the TGF-beta 1 precursor localized to large fibrillar structures in the extracellular matrix. The appearance of these fibrillar structures preceded the appearance of type I collagen fibers. Plasmin treatment abolished the fibrillar staining pattern for LTBP and released a complex containing both LTBP and TGF-beta. Antibodies and antisense oligonucleotides against LTBP inhibited the formation of mineralized bonelike nodules in long-term fetal rat calvarial cultures. Immunohistochemistry of fetal and adult rat bone confirmed a fibrillar staining pattern for LTBP in vivo. These findings, together with the known homology of LTBP to the fibrillin family of proteins, suggest a novel function for LTBP, in addition to its role in matrix storage of latent TGF-beta, as a structural matrix protein that may play a role in bone formation.
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              Role of transforming growth factor-beta1 and its latent form binding protein in pseudoexfoliation syndrome.

              Pseudoexfoliation (PEX) syndrome is a common and clinically important systemic condition characterized by the pathologic production and accumulation of an abnormal fibrillar extracellular material in many intra- and extraocular tissues. Recent evidence suggests that it is a type of elastosis associated with the excess synthesis of elastic microfibrillar components such as fibrillin-1. Since transforming growth factor (TGF)-beta is a major modulator of extracellular matrix formation, the potential involvement of TGF-beta and its latent form binding protein (LTBP) in this aberrant matrix process was investigated. The expression of various isoforms of TGF-beta and LTBP was investigated in the anterior segment tissues of PEX and control eyes on the protein and mRNA level by light and electron microscopic immunohistochemistry, in situ hybridization, and semiquantitative RT-PCR. TGF-beta1 and TGF-beta2 levels were measured in aqueous humor and serum of PEX and control patients by ELISA. Cultures of Tenon's capsule fibroblasts were established to study the effect of TGF-beta1 on fibrillin-1 mRNA expression by Northern blot analysis. Significantly increased concentrations of both total and active TGF-beta1 were measured in the aqueous humor of PEX eyes without and with glaucoma as compared to control eyes, whereas levels of TGF-beta2 were not significantly different. The expression of TGF-beta1, LTBP-1, and LTBP-2, but not TGF-beta2, was markedly increased in anterior segment tissues of PEX eyes, particularly in the non-pigmented epithelium of the ciliary body, on both the mRNA and the protein level. Latent TGF-beta1 staining was consistently associated with PEX material deposits and could be released by proteolytic processing. Double immunolabeling revealed clear co-localization of LTBP-1 and -2 with latent TGF-beta1 and with fibrillin-1 on PEX fibrils. The expression of mRNA coding for fibrillin-1 was up-regulated in vitro by TGF-beta1. This study provides evidence for a significant role of TGF-beta1 and the LTBPs 1 and 2 in PEX syndrome. The results suggest that increased levels of latent and active TGF-beta1 in the aqueous humor of PEX patients, derived from enhanced local synthesis and activation, promote the buildup of the abnormal extracellular elastic material characteristic of PEX syndrome. They further support a dual role for LTBPs, both as integral structural components of PEX fibers and as a means of matrix anchorage of latent TGF-beta1, representing one possible mechanism for the regulation of TGF-beta1 activity in PEX eyes. Future therapeutic strategies might focus on TGF-beta1 antagonistic approaches. Copyright 2001 Academic Press.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                February 2006
                11 November 2005
                : 102
                : 3-4
                : e99-e104
                aChildren’s Hospital and bDepartment of Medicine IV, University of Erlangen-Nuremberg, Erlangen, cDepartment of Nephrology, University of Kiel, Kiel, Germany; dDepartment of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, Canada
                89688 Nephron Exp Nephrol 2006;102:e99–e104
                © 2006 S. Karger AG, Basel

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                Figures: 3, References: 17, Pages: 1
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