Fibrillin 1 abnormalities in dermal fibroblast cultures from first‐degree relatives of patients with systemic sclerosis (scleroderma)

Wallis, Debra D.; Tan, Filemon K.; Kessler, Remi A.; Kimball, Misty D.; Cretoiu, Jill S.; Arnett, Frank C.; Milewicz, Dianna M.

doi:10.1002/art.11437

Cited by 12 publications

(8 citation statements)

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“…Our previous studies indicated that some autoantibodies to fibrillin-1 in SSc sera, but not all, are directed against a 30-kDa glutathione fusion protein containing the proline-rich C region of human fibrillin-1 (11,12). The recombinant peptide (aa 378 -495) in this study was cloned by RT-PCR from normal human fibroblast RNA and expressed in the pBADThio (Invitrogen Life Technologies) vector as a thioredoxin fusion protein with a C-terminal polyhistidine tag.…”

Section: Recombinant Fibrillin-1 Ag and Anti-fibrillin-1 Autoantibodiesmentioning

confidence: 99%

“…In cultured fibroblasts from SSc patients, fibrillin-1 is synthesized and secreted normally into the ECM, but the fibrillin-1-containing microfibrils are unstable and turn over more rapidly when compared with microfibrils from control fibroblasts (10). First-degree relatives of patients with SSc also have the same microfibril instability, suggesting that this is an inherent genetic defect (11). Theoretically, a breakdown of fibrillin-1-containing microfibrils could lead to release of TGF-␤ sequestered in microfibrils (8).…”

Section: S Cleroderma or Systemic Sclerosis (Ssc)mentioning

confidence: 99%

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Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Zhou

Tan

Milewicz

et al. 2005

The Journal of Immunology

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Fibroblasts from patients with systemic sclerosis (SSc) are activated producing excessive amounts of extracellular matrix (ECM) components. Recently, we identified a new SSc-specific autoantibody against portions of fibrillin-1, a major component of ECM microfibrils and regulator of TGF-β1 signaling. To examine a potential pathogenic role of anti-fibrillin-1 autoantibodies, normal human fibroblasts were treated with affinity-purified autoantibodies isolated from SSc sera and then examined for alterations in gene and protein expression levels using microarrays, quantitative RT-PCR, immunoblots, and immunofluorescence. Compared with fibroblasts cultured in normal medium or in medium containing normal human IgG, anti-fibrillin-1 autoantibody-treated normal dermal fibroblasts showed increased expression of COL and several other ECM components characteristically overexpressed in SSc fibroblasts. This was accompanied by phosphorylation and nuclear translocation of Smad3. Neutralization of TGF-β1 with anti-TGF-β1 Abs significantly diminished the activation of fibroblasts by anti-fibrillin-1 autoantibodies. These data indicate that anti-fibrillin-1 autoantibodies can induce the activation of normal dermal fibroblasts into a profibrotic phenotype resembling that of SSc by potentially causing the release of sequestered TGF-β1 from fibrillin-1-containing microfibrils in the ECM.

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Section: Recombinant Fibrillin-1 Ag and Anti-fibrillin-1 Autoantibodiesmentioning

confidence: 99%

Section: S Cleroderma or Systemic Sclerosis (Ssc)mentioning

confidence: 99%

Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Zhou

Tan

Milewicz

et al. 2005

The Journal of Immunology

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“…27 Moreover, abnormalities in structural integrity and assembly have been recognized in fibrillin 1-containing microfibrils in the ECM of primary dermal fibroblasts explanted from scleroderma patients. 28 Finally, elevated levels of TIMP1 and TIMP2, inhibitors of MMP2, have been observed in scleroderma fibroblasts and patients' sera. 29…”

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confidence: 99%

THIS ARTICLE HAS BEEN RETRACTED Elevated expression of isopeptide bond cross-links contributes to fibrosis in scleroderma and the healing wounds of tight skin mice

Sullivan¹,

Kakati²,

Carter³

et al. 2008

Wound Repair and Regeneration

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Scleroderma is a chronic disease characterized by excessive tissue fibrosis. Recent studies indicate that cultured dermal fibroblasts isolated from patients produce excessive amounts of collagen and other extracellular matrix components. In this study, we investigated the mechanism(s) of abnormal extracellular matrix accumulation in the scleroderma biopsies and the healing wounds of Tsk1/+ mice. Full-thickness excisional wounds were made in Tsk1/+ and wild-type mice and were subsequently harvested at days 7, 10, and 14 postinjury. The levels of profibrotic cytokine, transforming growth factor were elevated in the wounds of Tsk1/+ mice. Interestingly, the levels of matrix metalloproteinase were significantly reduced in the granulation tissue of Tsk1/+ mice in comparison with wild-type. Furthermore, immunohistochemical analysis of the wounds indicated that the levels of γ-glutamyl-ε-lysine cross-links were elevated in the granulation tissue of Tsk1/+ mice as well as the fibrotic lesions of scleroderma specimens. Collectively, these findings indicate that elevated collagen synthesis and decreased matrix metalloproteinase levels, in combination with increased isopeptide bond cross-links, contribute to abnormal collagen synthesis and assembly in granulation tissue of Tsk1/+ mice and the fibrotic lesions of scleroderma patients.Scleroderma is an intricate disorder of connective tissue that initially affects the skin but later also involves internal organs such as the kidneys, lungs, gastrointestinal tract, and cardiovascular system. 1 The key morphological features are (a) structural and functional vascular abnormalities, (b) mononuclear cellular infiltrates that very likely reflect an autoimmune disturbance, and (c) increased deposition of newly synthesized matrix, mainly type I collagen. 1 The morbidity of scleroderma largely depends upon a third facet of the disease -fibrosis. Recent studies have focused on identifying the ways in which different cellular components interact to culminate in the major vascular and fibrotic pathology of scleroderma. 2,3 Experimental evidence from in vitro and in vivo analyses of cells and tissues from scleroderma patients, as well as from animal models, point to a complex cascade of primary and secondary mediators. 4,5Perhaps the most striking feature of the pathology in scleroderma is the excessive deposition of extracellular matrix (ECM) components, which is the basis for the destruction of normal tissue architecture that leads to tissue and organ dysfunction. 6,7 Collagen is the predominant component of the ECM and is synthesized and secreted by fibroblasts. It has been demonstrated that cultured dermal fibroblasts from scleroderma patients produce more collagen type I and

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“…Récemment, la surexpression de TGF-BRI dans une souris transgénique entraînant une fibrose cutanée et des anomalies vasculaires proches de celles qui caractérisent la ScS, confirme l'implication de cette voie [15]. Peu de travaux ont porté sur l'analyse protéique mais une instabilité de la protéine FBN-1 et des microfibrilles chez les patients ScS ainsi que chez leurs apparentés au premier degré a été suggérée [18]. Par ailleurs, des auto-anticorps dirigés contre la fibrilline-1 ont été décrits chez les patients ScS ; ceux-ci auraient la capacité d'induire un phénotype profibrotique dans des fibroblastes [19].…”

Section: Fibrilline-1 Tgf-b Et Syndrome De Marfanunclassified

Interactions entre la Fibrilline-1 et le TGF-β

2009

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Fibrillin 1 abnormalities in dermal fibroblast cultures from first‐degree relatives of patients with systemic sclerosis (scleroderma)

Cited by 12 publications

References 8 publications

Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

THIS ARTICLE HAS BEEN RETRACTED Elevated expression of isopeptide bond cross-links contributes to fibrosis in scleroderma and the healing wounds of tight skin mice

Interactions entre la Fibrilline-1 et le TGF-β

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Fibrillin 1 abnormalities in dermal fibroblast cultures from first‐degree relatives of patients with systemic sclerosis (scleroderma)

Cited by 12 publications

References 8 publications

Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

THIS ARTICLE HAS BEEN RETRACTED Elevated expression of isopeptide bond cross-links contributes to fibrosis in scleroderma and the healing wounds of tight skin mice

Interactions entre la Fibrilline-1 et le TGF-β

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THIS ARTICLE HAS BEEN RETRACTED Elevated expression of isopeptide bond cross-links contributes to fibrosis in scleroderma and the healing wounds of tight skin mice