Up‐regulation of the extracellular matrix remodeling genes, biglycan, neutrophil gelatinase‐associated lipocalin and matrix metalloproteinase‐9 in familial amyloid polyneuropathy

Sousa, Mónica Mendes; Amaral, Barbas do; Guimarães, António; Saraiva, Maria João

doi:10.1096/fj.04-2022fje

Cited by 66 publications

(67 citation statements)

References 37 publications

(46 reference statements)

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“…In FAP-patient salivary gland tissue, HNE was increased by approximately 50% compared with controls ( Figure 1A); the immunostaining was exclusively cytoplasmic and was present in epithelial cells in salivary gland excretory ducts, at the same location of TTR fibrillar amyloid deposits (13). This result is in accordance with a previous report of the involvement of lipid peroxidation in colon biopsies of FAP patients (15).…”

Section: Tissue Markers For Oxidative Stresssupporting

confidence: 91%

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Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy

Macedo

Batista

Amaral

et al. 2007

Mol Med

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The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2′-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization.

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Section: Tissue Markers For Oxidative Stresssupporting

confidence: 91%

“…Labial minor salivary gland biopsy specimens were obtained from V30M FAP patients before they underwent liver transplantation (13), the only available treatment for this disorder. Control salivary gland tissue samples were from non-FAP volunteer individuals who had no evidence of infection.…”

Section: Human Samplesmentioning

confidence: 99%

Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy

Macedo

Batista

Amaral

et al. 2007

Mol Med

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“…NGAL is currently one of the most interesting and enigmatic proteins involved in tumor development (10). Previous studies have shown that NGAL has a role in extracellular matrix remodeling and can protect matrix metalloproteinase-9 (MMP-9) from degradation by interacting with NGAL (11,12). In patients with breast cancer, a high-molecular-weight complex consisting of NGAL and MMP-9 has been found in urine samples (13), and elevated NGAL expression is associated with decreased survival (14).…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of neutrophil gelatinase-associated lipocalin in oral squamous cell carcinoma: Relation to cell differentiation

Noguchi¹

2011

Oncol Rep

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Abstract. Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin2, LCN2) is a secreted glycoprotein with increased expression in solid tumors. The expression and functions of NGAL in oral cancer, however, remain unclear. We investigated the expression of NGAL in oral cancer tissues and oral cancer cell lines. By immunohistochemical examinations, NGAL expression was strongly up-regulated in well-differentiated OSCC tissues and moderately to weakly up-regulated in moderately to poorly differentiated OSCC tissues. In contrast, NGAL expression was weak or very weak in normal mucosa and leukoplakia. By Western blot analysis, NGAL expression levels positively correlated with cell morphology patterns and loss of E-cadherin. In addition, the enzymatic activity of the NGAL/MMP-9 complex significantly correlated with the results obtained by zymographic analysis. In conclusion, NGAL expression is high in welldifferentiated cancer, suggesting that NGAL may be a useful diagnostic marker of tumor-cell differentiation.

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“…MMPs 2, 3, and 9 were shown to degrade Ab fibrils in vitro, 32 and are upregulated in brain tissues obtained from Alzheimer's disease patients and transgenic model mice. 33 Similarly, MMPs degraded TTR fibrils and prefibrillar aggregates in vitro and were upregulated in FAP patients, 34 transgenic animals, 35 and a cultured cell line. 36 In this report, we show the capacity of fibroblasts to endocytose and degrade small TTR aggregates in lysosomes, both 'in vitro' and in an 'in vivo' model, after s.c. injection of TTR aggregates into WT mice, whereby soluble and aggregated TTR were endocytosed by fibroblasts and macrophages that efficiently cleared both types of TTRs with time.…”

Section: Role Of Fibroblasts In Ttr Amyloidosis Y Misumi Et Almentioning

confidence: 98%

Fibroblasts endocytose and degrade transthyretin aggregates in transthyretin-related amyloidosis

Misumi

Ando

Gonçalves

et al. 2013

Laboratory Investigation

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Transthyretin (TTR)-related amyloidosis is a fatal disorder characterized by systemic extracellular deposition of TTR amyloid fibrils. Mutations in the TTR gene cause an autosomal dominant form of the disease-familial amyloidotic polyneuropathy (FAP). Wild-type (WT) TTR can also form amyloid fibrils in elderly patients with senile systemic amyloidosis. Regression of amyloid deposits in FAP patients who undergo liver transplantation to remove the main source of mutant TTR suggests the existence of mechanisms for the clearance of TTR deposits from the extracellular matrix (ECM), but the precise mechanisms are largely unknown. Because fibroblasts are abundant, playing a central role in the maintenance of the ECM and because the skin is one of the major sites of soluble TTR catabolism, in the present study, we analyzed their role in clearance of TTR aggregates. In vitro studies with a fibroblast cell line revealed that fibroblasts endocytosed and degraded aggregated TTR. Subcutaneous injection of soluble and aggregated TTR into WT mice showed internalization and clearance over time by both fibroblasts and macrophages. Immunohistochemical studies of skin biopsies from V30M patients, asymptomatic carriers, recipients of domino FAP livers as well as transgenic mice for human V30M showed intracellular TTR immunoreactivity in fibroblasts and macrophages that increased with clinical status and with age in transgenic mice. Overall, the present in vitro and in vivo data show that fibroblasts endocytose and degrade TTR aggregates. The function or dysfunction of TTR clearance by fibroblasts may have important implications for the development, progression, and regression of TTR deposition in the ECM. KEYWORDS: amyloidosis; endocytosis; extracellular matrix; familial amyloidotic polyneuropathy; fibroblasts; transthyretin; TTR degradation Transthyretin (TTR)-related amyloidoses are fatal systemic amyloidoses associated with systemic deposition of TTR extracellular amyloid fibrils. TTR-related familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disease related to mutant TTR deposition in various organs and systems, including the peripheral nervous system, eyes, heart, gastrointestinal tract, kidneys, and skin. As of 2012, more than 120 TTR mutations have been discovered, most of which lead to FAP development (http://www.fapwtr.org/ ram_fap.htm); TTR V30M is the most common diseasecausing mutation and occurs in large foci of patients throughout the world. 1 Senile systemic amyloidosis (SSA) is an age-related nonhereditary systemic amyloidosis and mainly affects cardiac functions in elderly people where wild-type (WT) TTR forms amyloid in different tissues. 2 TTR is primarily synthesized by the liver, retina, and choroid plexus of brain, circulates as a soluble tetramer form in blood, cerebrospinal fluid, and aqueous humor, and transports thyroxine and retinol-binding protein. TTR dissociation into monomers is a determining step for partial misfolding, oligomer formation, and fibrillogenesis in tissues. The rate of T...

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Up‐regulation of the extracellular matrix remodeling genes, biglycan, neutrophil gelatinase‐associated lipocalin and matrix metalloproteinase‐9 in familial amyloid polyneuropathy

Cited by 66 publications

References 37 publications

Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy

Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy

Up-regulation of neutrophil gelatinase-associated lipocalin in oral squamous cell carcinoma: Relation to cell differentiation

Fibroblasts endocytose and degrade transthyretin aggregates in transthyretin-related amyloidosis

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