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PubMed1987

[Clinical value of determining the amino terminal fragment of procollagen III in myeloproliferative disorders].

The amino-terminal fragment of procollagen III was assayed by RIA in 186 patients with myeloproliferative disorders, at intervals of 6 to 24 months. The present results suggest that this assay may be useful for discriminating primary and secondary erythrocytosis, for evaluating the evolution of polycythemia vera towards spent phase and/or myelofibrosis, and for estimating the degree of myelofibrosis in patients with myeloid metaplasia of the spleen. However the methodology of the assay still needs technical improvements. An assay of procollagen I is needed. Excessive values of serum procollagen III may be due to hepatic or pulmonary fibrosis. Finally we don't have as yet a follow-up delay long enough to ascertain the prognostic value of the assay in polycythemia vera and in primary myelofibrosis.

Humans↗
PubMed1986

Localization of the human procollagen alpha 1(IV) gene to chromosome 13q34 by in situ hybridization.

Type IV (alpha 1 and alpha 2 chains) appears to be the only procollagen present in basement membranes. The structure of this protein is highly divergent from the interstitial and type V procollagens as exemplified by the interruptions in the Gly-X-Y region and unprocessed amino and carboxyl noncollagenous peptides. To expand our knowledge concerning the primary sequence of type IV and to investigate the factors influencing its unique distribution, we recently isolated cDNA clones coding for part of the human alpha 1(IV) chain. To determine if the alpha 1(IV) gene was cytologically linked to other procollagen genes that have been assigned to autosomes 17, 12, 7, and 2, overlapping clones covering 2.6 kilobases (kb) of the alpha 1(IV) mRNA were used together for in situ hybridization to human metaphase chromosomes. Here, we show precise localization of alpha 1(IV) at the telomere of 13q, thereby defining a fifth chromosome that contains members of this large and surprisingly dispersed multigene family.

Amino Acid Sequence↗
PubMed1986

Serum concentrations of N-terminal propeptide of type III procollagen and laminin in the outflow of fibrotic livers compared with liver-distal regions.

The immunoreactive serum concentrations of the basement membrane glycoprotein laminin, including its split product (pepsin-resistant fragment P1), and of the aminoterminal propeptide of type III procollagen, were measured in liver outflow (hepatic vein) and in liver-distal venous (renal vein) and arterial (femoral artery) regions in liver cirrhotic and fibrotic patients (n = 40). In the majority of patients with liver fibrosis and cirrhosis (0.52 to 0.69) the relatively highest concentrations of laminin (2.09 U/ml, p less than 0.05) and of procollagen propeptide (28.5 ng/ml, p less than 0.001) were found in the hepatic vein. No significant correlations were observed between the concentrations of the two biomatrix proteins in either region of the circulation, but a highly positive statistical correlation (r = 0.9425) was found between the level of laminin in the hepatic vein of cirrhotic subjects and portal venous pressure. The respective correlations were lower for laminin measured in the renal vein and the femoral artery. The concentration of procollagen propeptide was statistically not related to the portal venous pressure.

Blood Pressure↗
PubMed1985

Isolation of a new procollagen V chain from chick embryo tendon.

Whole tendons of chick embryos synthesize procollagens V which consist of three pro-alpha chains: pro-alpha 1'(V), pro-alpha 1(V) and pro-alpha 2(V). This report shows that while the pro-alpha 1'(V) chain is similar to the pro-alpha 1(V) chain in many respects, such as similar but not identical peptide maps, it also distinctly differs from it in size and in other ways. The new chain is denoted as pro-alpha 1' to indicate the relationship. We have failed to see conversion of one chain into the other and they are regarded as variants, although we do not know whether they are different transcripts of one gene or products of two closely related genes. The pro-alpha(V) chains are assembled into the disulfide-linked homotrimer (pro-alpha 1'(V))3 and the heterotrimer [(pro-alpha 1'(V)S-S-pro-alpha 2(V))pro-alpha 1(V)] and a smaller amount of [(pro-alpha 1(V)2pro-alpha 2(V)]. The pro-alpha 1'(V) chains are processed similarly to the pro-alpha 1(V) by the initial removal of the presumed carboxyl propeptide yielding p-alpha 1'(V) and then by reduction in the size of the noncollagenous, presumed amino propeptide to yield alpha 1'(V). A size difference between the alpha 1'(V) and alpha 1(V) series of molecules is demonstrated by velocity sedimentation and by electrophoretic mobility of the reduced molecules. This difference is ascribed to a difference in the size of the propeptides because after pepsin digestion the products of both series of molecules are the same size and electrophorese like alpha 1(V)(pepsin). The carboxyl propeptides of pro-alpha 1(V) and pro-alpha 1'(V) are the same size, but the amino propeptide of pro-alpha 1'(V) is smaller than that of pro-alpha 1(V). The amino propeptide of pro-alpha 1'(V) and p-alpha 1'(V) also lacks asparagine-linked complex carbohydrate, which is linked to propeptides of the p-alpha 1(V) and p-alpha 2(V) chains. Differences between the alpha 1(V) and alpha 1'(V) series of molecules remain in material synthesized in the presence of tunicamycin. Primary cultures of tendon cells synthesize procollagen V consisting of the above three chains, but the procollagen V made by cultured tendon sheath synovial cells predominantly contains [(pro-alpha 1(V))2pro-alpha 2(V)].

Animals↗
PubMed1984

[Clinical significance of type III procollagen peptide in sera of patients with liver cancer].

We assayed type III procollagen peptide in the sera of 213 patients with various liver diseases and 23 normal controls by radioimmunoassay. The non-cancerous limit of the serum level of type III procollagen peptide was defined as the mean +/- 2 SD of the patients with chronic hepatitis, liver cirrhosis and alcoholic liver disease; it was 50 ng/ml. The percentage of type III procollagen peptide in sera exceeding this limit was 22.2% in patients with hepatocellular carcinoma and 17.4% in metastatic liver cancer. Only patients with liver cirrhosis accompanied by alcoholic hepatitis exceeded this limit. In patients with hepatocellular carcinoma with peptide concentrations above 50 ng/ml, the serum level of GOT, GPT, LDH, T. Bil., LAP, gamma-GTP and T. Chol. was significantly higher than in patients with hepatocellular carcinoma whose serum peptide level was below 20 ng/ml.

Alanine Transaminase↗
PubMed1982

In vitro synthesis of type IV procollagen.

Total RNA was isolated from parietal endoderm cells of 131/2-day mouse embryos that synthesize large amounts of type IV procollagen. In vitro translation of this RNA in the reticulocyte lysate supplemented with a ribonuclease inhibitor yielded two equally prominent polypeptides of Mr = 165,000 and 168,000, immunoprecipitable with anti-mouse type IV collagen serum. The Mr = 165,000 polypeptide was shown by one-dimensional peptide mapping to represent an unmodified chain of type IV procollagen. The Mr = 168,000 polypeptide, the in vitro synthesis of which was barely detectable in the absence of a ribonuclease inhibitor, most likely represents the other genetically distinct chain of type IV procollagen. Similar results to those described were also obtained using poly(A) + RNA prepared from murine F9 embryonal carcinoma cells induced to differentiate in vitro into parietal endoderm.

Animals↗
PubMed1981

Altered secretion of type III procollagen in a form of type IV Ehlers-Danlos syndrome. Biochemical studies in cultured fibroblasts.

Cultured dermal fibroblasts from a woman with one variety of type IV Ehlers-Danlos syndrome synthesized type III procollagen but fail to secrete the bulk of the protein. Although total collagen production is similar to that of controls, the affected cells retain almost twice as much collagen as controls. The additional retained protein is a disulfide-boned collagenous trimer that remains disulfide-linked after limited proteolysis with pepsin and, after pepsin treatment, migrates with type III collagen on polyacrylamide gel electrophoresis. Affected cells have markedly increased staining with antibodies directed against type III procollagen. These studies indicate that decreased secretion of type III procollagen that is synthesized can result in the clinical syndrome of type IV Ehlers-Danlos syndrome.

Adult↗
PubMed1983

Altered protein glycosylation and procollagen to collagen conversion in human fibroblasts.

Skin fibroblasts, from a 9-year-old girl with an apparent heritable disorder of connective tissue, were cultured in vitro. The biosynthesis of the extracellular matrix glycoproteins, procollagens, and fibronectin was studied using radioactively labeled sugars and amino acids. Glycoproteins synthesized and secreted into the growth medium were found to be only partially glycosylated and the extracellular limited proteolytic conversion of procollagen type I to collagen was impaired, with procollagen chains accumulating in the growth medium. These biosynthetic alterations have not been previously reported in human skin fibroblasts, but similar findings have been described in tunicamycin-treated chick fibroblasts.

Biological Transport↗
PubMed1980

Procollagens as markers for the cell of origin of human bone tumors.

Cells derived from osteogenic sarcomas and from Ewing's sarcomas, two malignant bone tumors, were examined for the types of collagens they elaborated into the tissue culture media. Type I procollagen was the predominant species from all osteogenic sarcoma cell lines, a finding consistent with bone cell origin. The Ewing's sarcoma cells contained a prominent peak of type III procollagen and resembled the profile of vascular smooth muscle cells. Fibroblasts derived from skin biopsies taken from amputation specimens synthesized both type I and type III procollagens at the expected ratio of approximately 3:1. The examination of matrix proteins may provide a general classification scheme for human sarcomas and permit distinction of one tumor from another, as well as from normal fibroblasts.

Bone Neoplasms↗
PubMed1980

[Anti-laminin and anti-type IV procollagen antibodies in Goodpasture's syndrome (author's transl)].

The sera of 24 patients presenting with Good-pasture's syndrome, and of 30 normal blood donors were tested for the presence of anti-basement membrane (BM) antibodies, by a radioimmunological method, using two highly purified BM antigens, i.e. the type IV (BM) procollagen and a non-collagenous glycoprotein (laminin) isolated from the BM matrix secreted by a murine tumor. In marked contrast to the normal sera, the sera from 20 out of 24 patients presenting with Goodpasture's syndrome exhibited high anti-laminin and/or anti-type IV procollagen antibody levels. The other sera did not react with both BM antigens tested. The antibody titers varied according to the antigens used the sera tested. Kidney eluates from 4 "positive" patients also contained significant amounts of anti-laminin and anti-type IV procollagen antibodies. The data demonstrate that, in Goodpasture's syndrome, the pathogenicity of circulating and kidney-fixed anti-BM antibodies is not related to the chemical nature of the BM antigens triggering the immune response only. They suggest a polyclonal rather than a monoclonal stimulation in this disease.

Anti-Glomerular Basement Membrane Disease↗
PubMed1980

Intracellular processing of procollagen induced by the action of colchicine.

Corium fragments incubated in vitro with colchicine or obtained from chick embryos 11 days old after in vivo injection of this alkaloid were studied with the electron microscope. The well known effect of colchicine in producing an accumulation of procollagen was demonstrated by electrophoretic separation of the collagenous products in polyacrylamide gels after incubation of corium fragments in vitro with labelled amino acids. Electron microscopical studies showed various types of cytoplasmic vacuoles containing collagenous fibrillar structures. Some of these vacuoles contained non-striated filaments, fibres with the periodicity of native collagen, and segment long spacing (SLS) crystallites, embedded in an electrondense substance. The central aspect of this communication is the finding of intracellular SLS in cytoplasmic vacuoles. These crystallites were morphologically intact, and had no additional bands at the NH2 or COOH ends, suggesting that they were formed by the aggregation of tropocollagen molecules. Since the presence of intact SLS in cytoplasmic vacuoles suggests that these are secretory, we believe that inhibition of the transcellular transport system by colchicine permitted the visualization of vacuoles containing the products of tropocollagen interconversions. We interpret these findings as an example of autophagocytosis, with intracellular processing of procollagen, occurring in chick embryo fibroblasts when the secretion of procollagen is inhibited by colchicine.

Animals↗
PubMed1994

The role of cysteine residues in the folding and association of the COOH-terminal propeptide of types I and III procollagen.

Procollagen chains assemble in a type-specific manner forming either homo- or heterotrimers. The molecular mechanisms underlying procollagen chain selectivity are unknown, although it is thought that the C-propeptide (COOH-terminal propeptide) is responsible for directing chain recognition and assembly. To define the processes involved in chain selection we reconstituted the initial stages of procollagen folding and assembly in a cell-free system. Using human pro-alpha 1(III) and pro-alpha 2(I) chains as prototypes of chains that are either capable or incapable of forming homotrimeric molecules, respectively, we constructed two minigenes (p alpha 1(III) delta 1 and p alpha 2(I) delta 1) that lacked most of the triple helical domains. The minigenes were transcribed in vitro and translated in a rabbit reticulocyte lysate supplemented with microsomal membranes under conditions that favored disulfide bond formation. Both pro-alpha 1(III) delta 1 and pro-alpha 2(I) delta 1 chains formed intrachain disulfide bonds within the C-propeptide. However, only pro-alpha 1(III) delta 1 chains were able to self-associate forming homotrimers stabilized by interchain disulfide bonds. The C-propeptide of the pro-alpha 1(III) chain contains 8 cysteine residues (Cys-1-8). We used a site-directed mutagenesis to investigate the role of specific cysteine residues in trimer formation and found that substitution of serine for Cys-1, Cys-2, Cys-3, and Cys-4 prevented interchain disulfide bonding and trimerization. Furthermore, mutations in Cys-1 and Cys-4 also prevented intrachain disulfide bond formation within the C-propeptide. The C-propeptide of the pro-alpha 2(I) chain contains only 7 cysteine residues, lacking cysteine at position 2. Substitution of the existing Ser residue with Cys did not produce a homotrimeric phenotype, indicating that additional recognition signals are required to determine chain selection.

Animals↗
PubMed1994

Localization of mRNA of procollagen alpha 1 type I in torn supraspinatus tendons. In situ hybridization using digoxigenin labeled oligonucleotide probe.

A tendon is predominantly composed of collagen Type I. To determine the synthesis of collagen Type I after a rotator cuff tear, an in situ hybridization technique was applied to localize cells containing procollagen alpha 1 Type I in the proximal stump of five torn supraspinatus tendons obtained during surgery. Specimens were fixed in 10% buffered formalin, embedded in paraffin, and sectioned at 6 microns. A 22 mer oligonucleotide corresponding to a sequence coding a part of human procollagen alpha 1 Type I messenger RNA (mRNA) was used as a hybridization probe. The probe was 3'-end labeled with digoxigenin-11-dUTP, and the probe-mRNA hybrids were enzymatically visualized using conventional chromogens for alkaline phosphatase. The procollagen alpha 1 type I mRNA was clearly observed in the cells near the margin of the tear. However, they were not consistently found in the vicinity of the intratendinous extension of the tear and in cells of the subacromial bursa. It is concluded that this method should be used to study the characteristics of collagen synthesis in a torn rotator cuff tendon.

Digoxigenin↗
PubMed1993

Synthetic peptide-based immunoassay for amino-terminal propeptide of type I procollagen: application for evaluation of bone formation.

Serum biochemical markers are powerful tools for the evaluation of bone turnover. In this study, we developed a radioimmunoassay, using a synthetic peptide for the N-terminal fragment of human type I [alpha 1(I)] procollagen (N-PCP). A 14-amino acid peptide was synthesized from the amino terminus and used to generate antibodies in rabbits. The synthetic peptide was used as standard and tracer in the assay. Both native type I amino procollagen (PINP), which was purified from skin fibroblasts, and human serum displaced tracer binding in parallel with the synthetic peptide. The range for measurement of N-PCP in serum was 0.7 to 30 micrograms/L (0.21-9.18 nmol/L). In a sample of 17 normal adults and 13 children (ages 9-16 years) there was a strong correlation between serum N-PCP determined by this assay and both skeletal alkaline phosphatase isoenzyme and osteocalcin, markers of bone formation. Serum concentrations of N-PCP in a group of normal children were eightfold higher than concentrations in normal adults, with no overlap between the two groups. N-PCP also correlated with C-terminal type I procollagen determined with a commercially available kit (r = 0.92).

Adolescent↗
PubMed1993

Effect of chronic iron overload on procollagen gene expression.

The pathogenesis of hepatic fibrosis and cirrhosis in genetic hemochromatosis may involve a direct effect of excess iron on collagen synthesis in the liver. To investigate this theory, we measured procollagen messenger RNA levels (types I, III and IV) in the livers of rats in which we produced chronic parenchymal iron overload by feeding them dietary carbonyl iron (2.5%, wt/wt) for up to 18 mo. This feeding resulted in predominantly parenchymal iron deposition in a periportal distribution similar to that seen in genetic hemochromatosis. Increased amounts of collagen fibrils were observed in iron-loaded livers on electron microscopy; all iron-loaded livers showed some periportal fibrosis. Although very high hepatic iron concentrations (range = 340 to 1,100 mumol/gm dry wt) were achieved in the carbonyl iron-loaded rats, we saw no consistent difference between steady-state messenger RNA levels for procollagens types I, III and IV in control and iron-loaded livers examined at five different time points up to 18 mo. Messenger RNA levels of the cytokine transforming growth factor-beta 1, which has been implicated as having a role in the production of extracellular matrix proteins, were also measured. No significant differences were observed between iron-loaded and control livers. These results suggest that excess parenchymal iron does not have a direct effect on the expression of the procollagens or transforming growth factor-beta 1 genes in iron-loaded livers and that factors other than, or in addition to, iron are necessary for fibrosis to occur.

Animals↗
PubMed1996

[N-terminal peptide of type III procollagen in serum and bronchoalveolar fluid as a marker of collagen metabolism in chronic interstitial lung diseases].

Altered metabolism of collagen and its excessive deposition in the matrix of the connective tissue is a hallmark of chronic interstitial lung diseases. Since fibrosis frequently determines the course and prognosis of these diseases, a noninvasive test for assessment of pulmonary fibrosis would be very helpful. For instance, biochemical parameters which are correlated with collagen metabolism may be very helpful to monitor fibrosis. Type III procollagen N-terminal peptide (PIIIP), a peptide released during the conversion of type III procollagen to type III collagen is considered a potential marker of fibroblast activity in a variety of pulmonary and extrapulmonary diseases. In recent years an assay for the PIIIP has been used to assess collagen turnover both in serum and bronchoalveolar lavage fluid from patients with numerous chronic interstitial lung diseases. It is a review of recent studies on the value of determination of type III procollagen aminopeptide in serum and bronchoalveolar fluid in chronic interstitial lung diseases. On the basis of these reports the value of PIIIP as a marker of fibrosis in this group of lung diseases still remains controversial. The investigations on this subject are continued.

Biomarkers↗
PubMed1997

Transforming growth factors-beta 1, -beta 2, and -beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis.

Transforming growth factor (TGF)-beta 1 may potentiate wound healing and fibrosis by stimulating fibroblast collagen deposition. TGF-beta 1 is implicated in the pathogenesis of pulmonary fibrosis, but the role of TGF-beta 2 and TGF-beta 3 remains unclear. We examined their effects on lung fibroblast procollagen metabolism in vitro and localized their gene expression during bleomycin-induced lung fibrosis using in situ hybridization with digoxigenin-labeled riboprobes. All three isoforms stimulated fibroblast procollagen production. TGF-beta 3 was the most potent and also reduced procollagen degradation. In normal mouse lung, TGF-beta 1 and TGF-beta 3 mRNA transcripts were abundant in bronchiolar epithelium. After bleomycin, TGF-beta 1 gene expression was maximally enhanced at 10 days, with the signal being predominant in macrophages. Signal was also enhanced in mesenchymal, pulmonary endothelial, and mesothelial cells. After 35 days, the pattern of TGF-beta 1 gene expression returned to that of control lung. TGF-beta 3 gene expression remained unchanged throughout compared with controls. TGF-beta 2 mRNA was not detected with the antisense probe, but signal obtained with the sense probe suggests the presence of a naturally occurring antisense. This study demonstrates that TGF-beta 1, -beta 2, and -beta 3 all exert profibrotic effects in vitro. However, TGF-beta isoform gene expression is differentially controlled during experimental pulmonary fibrosis with TGF-beta 1 the predominant isoform expressed during pathogenesis.

Animals↗
PubMed1976

In vitro utilization of exogenous procollagen by embryonic tooth germs.

Embryonic mouse tooth germs treated with L-azetidine-2-carboxylic acid cease their development, undergo a regression of the enamel organ, and do not maintain the histological characteristics of the explanted dental organ. On the other hand if procollagen is added exogenously to explants continously treated with L-azetidine, the effects of the inhibitor are not seen and the tissue is maintained. Thus, exogenously supplied procollagen supports morphogenesis in tooth rudiments that are unable to synthesize procollagen.

Animals↗