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PubMed1998

Corticomedullary procollagen alpha1(IV) mRNA levels and localization after subtotal nephrectomy.

The relationships between tubular hypertrophy/hyperplasia, procollagen alpha1(IV) mRNA levels, and the development of tubular basement membrane thickening were studied in male Sprague-Dawley rats subjected to subtotal renal ablation and sacrificed 2 or 15 days later. Tubular hypertrophy and hyperplasia were demonstrable at 2 days, however no increment in procollagen alpha1 (IV) mRNA levels was discerned at that time, demonstrating a dissociation between mRNA levels for classical type IV collagen and tubular enlargement. At 15 days, tubular procollagen alpha1(IV) mRNA levels did increase approximately 2-fold (p < 0.002), localizing predominantly in proximal tubules in the deep cortex and outer medullary stripe. At this time point, there was still no significant correlation to tubular enlargement, but there was a significant correlation to tubular basement membrane thickening (r = 0.89, p < 0.01). These studies demonstrated that an increase in mRNA for classical type IV collagen is not required for the development of hypertrophy, and that the increment is a better marker for matrix expansion than it is for hypertrophy.

Actins↗
PubMedDate not supplied

Endothelial cells from umbilical vein and a hemangioendothelioma secrete basement membrane largely to the exclusion of interstitial procollagens.

The biosynthesis of extracellular matrix proteins by primary cultures of endothelial cells from human umbilical vein, and by clones from a murine hemangioendothelioma, was studied and compared to that reported for endothelium cultured from other sources. Umbilical vein endothelial cells secreted two glycoproteins-fibronectin and thrombospondin-which comprise the major proportion of the protein in the culture media of bovine aortic, venous, and corneal endothelial cells. These biosynthetic products were absent from hemangioendothelioma cultures. However, in contrast to bovine endothelium from large vessels and cornea, which secrete primarily Type III procollagen into the culture medium, both the umbilical vein and hemangioendothelioma cultures secrete Type IV (basement membrane) procollagen. In addition, EC, a novel endothelial collagen type that has been characterized in bovine endothelial cell supernates, was not present in the umbilical vein or tumor-derived endothelium. The production of basement membrane procollagen as the major collagen type in the medium of these cultures probably reflects the nature of the vascular bed from which the endothelial cells originated, rather than differences in species of in cellular isolation and subculture. We suggest that endothelial cells from different vascular environments could display variations in growth, migration, morphology, and response to exogenous blood-borne factors as a result of their relationship to an extracellular matrix/subendothelium composed of diverse structural glycoproteins.

Animals↗
PubMed1988

Increased procollagen III aminoterminal peptide-related antigens and fibroblast growth signals in the lungs of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by an increased density of inflammatory cells, fibroblasts, and collagen within the lung parenchyma. To gain insights into the mechanisms leading to the increased density of fibroblasts and altered collagen metabolism in the IPF lung, bronchoalveolar lavage fluid from normal subjects and patients with IPF or sarcoidosis was analyzed for (1) the presence of antigenic material related to the aminoterminal propeptide domain of type III procollagen, and (2) fibroblast growth-promoting activity in the extracellular milieu of the lower respiratory tract. Whereas bronchoalveolar lavage fluid (BALF) type III procollagen aminoterminal peptide-related antigen levels in 59 patients with sarcoidosis were similar to the levels of control subjects (p greater than 0.10), 31 patients with IPF had markedly increased levels (12-fold over controls; p less than 0.025, IPF versus controls; p less than 0.01, IPF versus sarcoidosis). Type III procollagen aminoterminal peptide-related antigen levels correlated with an increase in the ability of BALF to stimulate fibroblast proliferation (p less than 0.05). Furthermore, BALF from patients with IPF markedly stimulated human lung fibroblast proliferation in vitro (199% increase, p less than 0.01), whereas lavage fluid from patients with sarcoidosis and from control subjects did not. The enhanced fibroblast proliferation induced by IPF BALF occurred in the absence of serum and exogenous growth factors, suggesting that both competence- and progression-type growth factors were present in the lavage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Increased type I procollagen mRNA in airways and pulmonary vessels after vagal denervation in rats.

To test the hypothesis that increased airway strain resulting from lung denervation initiates a fibroproliferative response in the airways, we compared the transcriptional expressions of alpha1(I)-procollagen and tropoelastin in the lungs of rats subjected to unilateral vagal denervation, unilateral vagal denervation combined with ipsilateral phrenectomy, or thoracotomy without denervation (controls). We found increases in alpha1(I)-procollagen messenger ribonucleic acids (mRNAs) in the submucosa of the airways and the adventitia of airways and pulmonary vessels of the denervated lungs in 31% of the rats subjected to unilateral denervation (with and without phrenectomy), and in none of the controls. The increased transcripts were associated with collagen deposition in the peribronchial and perivascular tissue, and occasionally with cell proliferation leading to occlusion of the airway and vascular lumina. Unilateral phrenectomy did not decrease the frequency with which production of Type I procollagen was upregulated, suggesting that the upregulation was not entirely dependent on airway strain. Tropoelastin expression was not influenced by denervation. Our results indicate that the autonomic nervous system has a previously unsuspected trophic influence on collagen synthesis in the airways and pulmonary vessels. Abolition of this influence by denervation may lead to structural changes analogous to those observed in bronchiolitis obliterans after lung transplantation.

Animals↗
PubMed1999

Centriacinar remodeling and sustained procollagen gene expression after exposure to ozone and nitrogen dioxide.

Sprague-Dawley rats were exposed to 0.8 ppm ozone (O3), to 14.4 ppm nitrogen dioxide (NO2), or to both gases simultaneously for 6 h per day for up to 90 d. The extent of histopathologic changes within the central acinus of the lungs was compared after 7 or 78 to 90 d of exposure using morphometric analysis by placement of concentric arcs radiating outward from a single reference point at the level of the bronchiole- alveolar duct junction. Lesions in the lungs of rats exposed to the mixture of gases extended approximately twice as far into the acinus as in those exposed to each individual gas. The extent of tissue involvement was the same at 78 to 90 d as noted at 7 d in all exposure groups. At the end of exposure, in situ hybridization for procollagen types I and III demonstrated high levels of messenger RNA within central acini in the lungs of animals exposed to the combination of O3 and NO2. In contrast, animals exposed to each individual gas had a similar pattern of message expression compared with that seen in control animals, although centriacinar histologic changes were still significantly different from control animals. We conclude that the progressive pulmonary fibrosis that occurs in rats exposed to the combination of O3 and NO2 is due to sustained, elevated expression of the genes for procollagen types I and III. This effect at the gene level is correlated with the more severe histologic lesions seen in animals exposed to both O3 and NO2 compared with those exposed to each individual gas. In contrast, the sustained expression of the procollagen genes is not associated with a shift in the distribution of the lesions because the area of change in each group after 7 d of exposure was the same as after 78 to 90 d of exposure.

Animals↗
PubMed1988

Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII procollagen.

Epidermolysis bullosa acquisita (EBA) is a severe, chronic blistering disease of the skin. EBA patients have circulating and tissue-bound autoantibodies to a large (Mr = 290,000) macromolecule that is localized within the basement membrane zone between the epidermis and dermis of skin, the site of blister formation. The "EBA antigen" is known to be distinct from laminin, heparan sulfate proteoglycan, fibronectin, the bullous pemphigoid antigen, elastin, and collagen types I, II, III, IV, and V. Sera from patients with EBA, two monoclonal antibodies to the EBA antigen, and a monoclonal antibody to the carboxyl terminus of type VII procollagen identically label human amnion and skin by immunofluorescent and immunoelectron microscopy. Western immunoblots of the EBA antigen extracted from skin and of type VII procollagen labeled with the above sera and antibodies are identical. None of the sera or antibodies labels Western blots of pepsinized type VII collagen which is missing the globular amino and carboxyl terminal domains. These data show that the EBA antigen is the carboxyl terminus of type VII procollagen.

Amino Acid Sequence↗
PubMed1993

Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms.

Detailed DNA sequencing of the triple-helical domain of type III procollagen was carried out on cDNA prepared from 54 patients with aortic aneurysms. The 43 male and 11 female patients originated from 50 different families and five different nationalities. 43 patients had at least one additional blood relative who had aneurysms. Five overlapping asymmetric PCR products, covering all the coding sequences of the triple-helical domain of type III procollagen, were sequenced with 28 specific sequencing primers. Analysis of the sequencing gels revealed only two nucleotide changes that altered the structure of the protein. One was a substitution of threonine for proline at amino acid position 501 and its functional importance was not clearly established. The other was a substitution of arginine for an obligatory glycine at amino acid position 136. In 40 of the 54 patients, detection of a polymorphism in the mRNA established that both alleles were expressed. The results indicate that mutations in type III procollagen are the cause of only about 2% of aortic aneurysms.

Adult↗
PubMed1995

Stimulation of alpha 1 (I) procollagen gene expression in NIH-3T3 cells by the human T cell leukemia virus type 1 (HTLV-1) Tax gene.

The mechanisms that regulate the expression of genes encoding extracellular matrix proteins in fibroblasts and other mesenchymal cells have remained elusive. Studies from several laboratories have indicated that Tax, a trans-regulatory protein from the human T cell leukemia virus type I not only augments viral gene expression but also triggers the expression of various cellular genes. Here, we examined the hypothesis that the expression of collagen genes may also be modulated by Tax. NIH-3T3 cells were simultaneously transfected with a Tax expressor plasmid and a chimeric construct containing regulatory sequences (-804 to +42 bp) of the alpha 1(I) procollagen gene (COL1A1) promoter. The results indicated that the promoter activity of the -804 to bp COL1A1 fragment increased up to 12-fold in cells expressing Tax. Deletion analysis revealed that the region of COL1A1 encompassing nucleotides -174 to -84 contained the Tax-responsive elements. A gene segment encompassing nucleotides -187 to -67, which contained this region, proved sufficient to confer Tax inducibility (2.5-fold) to a herpes simplex virus thymidine kinase promoter. Stably transfected NIH-3T3 cell clones that constitutively produce Tax displayed elevated levels of alpha 1(I) procollagen and fibronectin transcripts and increased production and accelerated processing of type I procollagen. These findings suggest that retroviral proteins may be involved in the pathogenesis of idiopathic diseases accompanied by collagen overproduction.

3T3 Cells↗
PubMed1993

Clinical evaluation of serum aminoterminal propeptide of type III procollagen as tumor marker in gynecologic malignancies.

AIMS: The aim of this study was to determine the possible usefulness of the assay of the aminoterminal propeptide of type III procollagen and fibronectin in detecting connective tissue changes associated with gynecologic malignancies. STUDY DESIGN: Serum aminoterminal propeptide of type III procollagen and plasma fibronectin were measured in 36 women with gynecologic malignancies, 20 women with benign gynecologic tumors and 10 healthy women serving as controls. RESULTS: A significant serum propeptide was significantly high in the group with gynecologic malignancies and normal in the benign tumor group. The serum propeptide levels were related to of disease stage and presence of ascites in patients with ovarian carcinoma but not in those with cervical or endometrial carcinoma. In the follow-up study, a favorable clinical response was associated with normalizing propeptide levels whereas in rapidly progressive disease the levels fell initially but rose again. In partial response with ultimate progression, the propeptide concentration decreased but remained clearly above the normal range. No difference in plasma fibronectin was found among the malignant tumor, benign tumor and control groups. CONCLUSIONS: The present study indicates that the aminoterminal propeptide of type III procollagen could serve as an additional, non specific marker to follow the clinical behavior of gynecologic malignancies and consequently of connective tissue metabolism reflecting tumor matrix interaction.

Aged↗
PubMed1991

Serum concentrations of the type I and III procollagen propeptides as biochemical markers of growth velocity in healthy infants and children and in children with growth disorders.

The reproducibility and specificity of a new, rapid, simple RIA for measuring the concentration of the soluble carboxypropeptide of type I procollagen (PICP) in serum was confirmed. Serum PICP was determined in 442 healthy Caucasian subjects ranging in age from 3 wk to 18 y. Highest PICP values (mean +/- SD: 2200 +/- 350 micrograms/L) occurred in infants less than 3 mo of age, falling by 70% at 2 y and by an additional 10% at 4 y. There was no significant change in serum PICP between 4 and 16 y of age (330 +/- 130 micrograms/L), but a decrease to adult levels of less than 160 micrograms/L occurred by 18 y. In 76 children with growth disorders, serum PICP was related to linear growth velocity (p less than 0.001), although there were no significant differences in PICP among the 38 children with growth hormone insufficiency, the 21 short children with no endocrinologic abnormality, or the 17 tall children. All 15 prepubertal children treated with growth hormone for 3 mo showed significant increases in both growth velocity and serum PICP, with a significant relationship (p less than 0.01) between the degree of increases. The rise in serum PICP at 3 mo (but not baseline PICP values) predicted the increase in growth velocity after 1 y of treatment. Similar changes were observed in the concentration of the aminopropeptide of type III procollagen, except that serum aminopropeptide of type III procollagen showed a definite increase during puberty and a wider spread of values in growth disorders. We conclude that measuring serum PICP by the new, reproducible assay reflects height velocity in prepubertal children and may be a useful biochemical means of monitoring growth rates.

Adolescent↗
PubMed1990

Cortisol enhances the anabolic effects of insulin-like growth factor I on collagen synthesis and procollagen messenger ribonucleic acid levels in cultured 21-day fetal rat calvariae.

We examined the ability of cortisol to modulate the stimulatory effects of recombinant human insulin-like growth factor-I (IGF-I) on collagen synthesis, procollagen messenger RNA (mRNA) levels and DNA synthesis in 21-day fetal rat calvariae maintained in serum-free organ culture for 24-96 h. Collagen synthesis was quantitated by measuring the incorporation of [3H]proline into collagenase-digestible protein (CDP) and alpha-1(I) procollagen mRNA transcripts were assessed by Northern blot analysis. Cell replication was quantitated by measuring the incorporation of [3H]thymidine into bone. As described previously, 100 nM cortisol had a biphasic effect on CDP labeling, increasing CDP after 24 h and decreasing CDP after 48, 72, and 96 h of culture. IGF-I alone increased CDP labeling by 1.6-fold after 24 h and by 2-fold after 48 or 72 h of culture, and cortisol potentiated this anabolic effect. In the presence of 100 nM cortisol, IGF-I increased CDP labeling by 2.6-fold after 24 h, by 5-fold after 48 h, and by 8-fold after 72 h of culture. A higher concentration of cortisol (1000 nM) also potentiated the IGF-I response on CDP labeling after 96 h of culture. In the presence of 100 nM cortisol, concentrations of IGF-I lower than 10 nM consistently increased CDP labeling and the percent collagen synthesized whereas these concentrations were not always effective without cortisol. PTH, which like cortisol decreased basal CDP labeling, did not enhance the stimulatory effects of IGF-I. Cortisol also enhance the stimulatory effects of IGF-I on alpha-1(I) procollagen mRNA levels indicating that the potentiation of CDP labeling occurs via a pretranslational mechanism. IGF-I had little effect on the incorporation of [3H]thymidine into bone except in the presence of cortisol. Nevertheless, the ability of cortisol to potentiate the stimulatory effect of IGF-I on CDP labeling was independent of cell replication since the enhancement persisted in the presence of aphidicolin, a DNA synthesis inhibitor. Our findings show that physiological concentrations of cortisol can modulate the responsiveness of cells within cultured fetal rat calvariae to the anabolic effects of exogenous IGF-I.

Animals↗
PubMed1996

Failure of ventral body wall closure in mouse embryos lacking a procollagen C-proteinase encoded by Bmp1, a mammalian gene related to Drosophila tolloid.

The mouse bone morphogenetic protein1 (Bmp1) gene encodes a secreted astacin metalloprotease that cleaves the COOH-propeptide of procollagen I, II and III. BMP-1 is also related to the product of the Drosophila patterning gene, tolloid (tld), which enhances the activity of the TGFbeta-related growth factor Decapentaplegic and promotes development of the dorsalmost amnioserosa. We have disrupted the mouse Bmp1 gene by deleting DNA sequences encoding the active site of the astacin-like protease domain common to all splice variants. Homozygous mutant embryos appear to have a normal skeleton, apart from reduced ossification of certain skull bones. However, they have a persistent herniation of the gut in the umbilical region and do not survive beyond birth. Analysis of the amnion of homozygous mutant embryos reveals the absence of the fold that normally tightly encloses the physiological hernia of the gut. At the electron microscopic level, the extracellular matrix of the amnion contains collagen fibrils with an abnormal morphology, consistent with the incorporation of partially processed procollagen molecules. Metabolical labelling and immunofluorescence studies also reveal abnormal processing and deposition of procollagen by homozygous mutant fibroblasts in culture.

Amnion↗
PubMed2005

Procollagen trafficking, processing and fibrillogenesis.

Collagen fibrils in the extracellular matrix allow connective tissues such as tendon, skin and bone to withstand tensile forces. The fibrils are indeterminate in length, insoluble and form elaborate three-dimensional arrays that extend over numerous cell lengths. Studies of the molecular basis of collagen fibrillogenesis have provided insight into the trafficking of procollagen (the precursor of collagen) through the cellular secretory pathway, the conversion of procollagen to collagen by the procollagen metalloproteinases, and the directional deposition of fibrils involving the plasma membrane and late secretory pathway. Fibril-associated molecules are targeted to the surface of collagen fibrils, and these molecules play an important role in regulating the diameter and interactions between the fibrils.

Animals↗
PubMed2004

Development and clinical application in arthritis of a new immunoassay for serum type IIA procollagen NH2 propeptide.

Type II collagen, the most abundant protein of cartilage matrix, is synthesized as a procollagen molecule including the N-(PIINP) and C-(PIICP) propeptides at each end. Type II procollagen is produced in two forms as the result of alternative RNA splicing. One form (IIA) includes and the other form (IIB) excludes a 69-amino acid cysteine-rich globular domain encoded by exon 2 in PIINP. During the process of synthesis, these N-propeptides are removed by specific proteases and released in the circulation, and their levels are believed to reflect type II collagen synthesis. In this chapter we describe the development of a specific enzyme-linked immunosorbent assay (ELISA) for the measurement of the IIA form of PIINP (PIIANP) in serum based on a polyclonal antibody raised against recombinant human exon 2 fusion protein of type II procollagen. We show that this ELISA is highly specific for circulating PIIANP and has adequate technical precision. In patients with knee osteoarthritis and rheumatoid arthritis, serum PIIANP was decreased by 53% (p < 0.0001) and 35% (p < 0.001), respectively, suggesting that type IIA collagen synthesis is altered in these arthritic diseases. The measurement of serum PIIANP may be useful for the clinical investigation of patients with joint diseases.

Adolescent↗
PubMed1991

Aminoterminal propeptide of type III procollagen: a marker of disease activity in schistosomal patients.

The serum concentration of aminoterminal propeptide of type III procollagen was measured in 44 Egyptian healthy controls and 29 patients with hepatosplenomegaly originating from endemic areas for schistosomiasis in Egypt. Patients were classified into two main groups according to the histopathological pattern of the liver biopsy: patients with active schistosomal liver fibrosis and patients with inactive schistosomal liver fibrosis. Serum aminoterminal propeptide of type III procollagen levels were elevated in most of patients with active fibrosis but not in those with inactive schistosomiasis. From the present work, it is suggested that aminoterminal propeptide of type III procollagen can be used as a marker for active fibrogenesis in patients with schistosomal liver fibrosis.

Adolescent↗
PubMed1994

Serum carboxy-terminal propeptide of human type I procollagen in patients with primary hyperparathyroidism: studies in basal conditions and after parathyroid surgery.

This study was carried out in order to evaluate serum carboxy-terminal propeptide of human type I procollagen (PICP) in patients with primary hyperparathyroidism and to examine its changes following parathyroidectomy. Seventeen patients (four males and 13 famels, aged 53.8 +/- 3.1 SEM years) were studied in basal conditions; six patients also were investigated after successful parathyroid surgery. Mean serum PICP values of patients with primary hyperparathyroidism (194.5 +/- 27 SEM micrograms/l) were significantly higher (p < 0.001) with respect to those found in normal subjects. However, deviations from the norm (Z score values) were significantly less with respect to deviations of serum osteocalcin, alkaline phosphatase and urinary hydroxyproline/creatinine ratio. Following parathyroidectomy, it was possible to observe a discrepancy between markers of bone resorption and those of bone formation. The former tend to decrease, while the latter either do not show any significant change (serum alkaline phosphatase and serum osteocalcin) or increase (serum procollagen). The results of our investigation indicate that in basal conditions the assay of serum procollagen may be of clinical value but it would be better to use it in combination with other biomarkers of skeletal remodelling. The results obtained after parathyroidectomy are the opposite of those obtained following parathyroid hormone infusion and should be ascribed to the effect of acute hormone deficiency on collagen synthesis. The positive biochemical uncoupling following surgery might lend support to the rise of bone mineral density consistently reported in the first few months following parathyroidectomy.

Adenoma↗
PubMed1983

[Serum type III procollagen peptide in patients with pneumoconiosis].

Early diagnosis of lung fibrosis has been hampered by the lack of a simple, convenient and specific method. Recently Rohde et al. developed an assay method for Type III procollagen peptide. Type III procollagen peptide, an extension peptide released during the biosynthesis of collagen Type III, has been known as a good marker for hepatic fibrosis. Therefore, we applied this assay to the patients with idiopathic pulmonary fibrosis, lung fibrosis in collagen disease and silicosis. And also we measured the serum level of the peptide in the healthy workers being exposed to silica. Normal value of the peptide in adults was 8.3 +/- 2.6 (mean +/- SD; n = 32) ng/ml. The upper value over mean + 2SD, 13.4 ng/ml, was regarded as abnormal value. Six patients with idiopathic pulmonary fibrosis, and lung fibrosis in collagen disease showed a significant increased level of 19.0 +/- 9.6 ng/ml (P less than 0.02). Four of 6 patients had abnormal high values. On the other hand, the patients with silicosis had not so high levels of peptide (12.6 +/- 6.5 ng/ml; n = 24; P less than 0.01), but 25% of the patients showed abnormal values. There were 2 cases among 19 healthy workers being exposed to silica who revealed slight abnormal values, 15.6 and 16.7 ng/ml. These observations suggest that the assay has a prognostic value for lung fibrosis and also is useful for the early detection of active lung fibrosis in the workers, even though Type III procollagen biosynthesis is already low in the late stages of silicosis.

Adult↗
PubMed1992

Substitution of aspartate for glycine 1018 in the type III procollagen (COL3A1) gene causes type IV Ehlers-Danlos syndrome: the mutated allele is present in most blood leukocytes of the asymptomatic and mosaic mother.

A proband with arterial ruptures and skin changes characteristic of the type IV variant of Ehlers-Danlos syndrome was found to have a single-base mutation in the type III procollagen gene, which converted the codon for glycine at amino acid position 1018 to a codon for aspartate. (Amino acid positions are numbered by the standard convention in which the first glycine of the triple-helical domain of an alpha chain is number 1. The numbers of positions in the alpha 1(III) chains can be converted to positions in the human pro alpha(III) chain by adding 167.) Nucleotide sequencing of overlapping PCR products in which the two alleles were distinguished demonstrated that the mutation of glycine 1018 was the only mutation that changed the primary structure of type III procollagen. The glycine substitution markedly decreased the amount of type III procollagen secreted into the medium by cultured skin fibroblasts from the proband. It is surprising that the same mutation was found in about 94% of the peripheral blood leukocytes from the proband's asymptomatic 72-year-old mother. Other tissues from the mother contained the mutated allele; it was present in 0%-100% of different samples of hair cells and in about 40% of cells from the oral epithelium. Therefore, the mother was a mosaic for the mutation. Since the mutated allele was present in cells derived from all three germ layers, the results indicated that the mutation arose by the late blastocyst stage of development. The results also indicate that assays of blood leukocytes do not always reveal mosaicism or predict phenotypic involvement of tissues, such as blood vessels, that are derived from the same embryonic cells as are leukocytes.

Adult↗