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PubMed1982

Procollagen localisation in normal, premalignant and malignant lesions of the epidermis.

The distribution of procollagen in normal hyperplastic, preneoplastic or neoplastic human epidermal lesions has been analysed in indirect immunofluorescence tests with the antibodies to procollagen raised in sheep to extracted procollagen, synthesised by newborn rat skin explants in culture. These antiprocollagen antibodies produced indirect immunofluorescence staining only of the papillary dermis of human skin. We reacted serial dilutions of the antibody with each skin lesion and recorded the maximum dilution at which a positive reaction was observed. All lesions examined displayed essentially the same procollagen immunofluorescence pattern. The fluorescence was localised as a fibrillar/diffuse area just under the epidermis. In conditions in which the epidermis is highly convoluted, the fluorescent band was found to follow the pattern of the epidermis and to surround epidermal 'islands' in the deeper dermis. Our observations suggest that in the neoplastic lesions a new dermal topography, resembling the stratum papillare of normal human skin, is found in the deeper dermis surrounding the epidermal islands produced as the epidermal mass increases and invaginates further into the stroma. Malignant epidermal lesions were found to show a positive procollagen immunofluorescent staining at tenfold lower concentrations of the antibody than normal human skin in subepidermal regions.

Animals↗
PubMed1983

Assignment of the genes for mouse type I procollagen to chromosome 16 using mouse fibroblast-Chinese hamster somatic cell hybrids.

Somatic cell hybrids between mouse and Chinese hamster fibroblasts have been used to identify the chromosome responsible for the synthesis of both mouse type I procollagen subunit chains (MCOLA1 and MCOLA2). Thirty-one separate hybrid clones and subclones from ten separate hybridization events were isolated in hypoxanthine-aminopterin-thymidine (HAT) selection medium and were used for detailed gene-mapping studies. ELISA and "Western blotting" immunochemical analysis were used to detect the production of mouse type I procollagen in each hybrid clone. Mouse and Chinese hamster chromosomes were identified in each hybrid clone by trypsin-Giemsa banding of metaphase chromosome spreads and by isozyme analysis. We have found that mouse type I procollagen production segregates concordantly with mouse superoxide dismutase-1, previously mapped to mouse chromosome 16, and with the presence of mouse chromosome 16 karyotypically. Western blotting immunochemical analysis of the separated mouse procollagen chains produced by each hybrid line demonstrated that apparently the genes for both subunit chains are located on the same chromosome. These studies, therefore, assign the structural genes for mouse type I procollagen pro alpha 1 (MCOLA1) and pro alpha 2 (MCOLA2) chains to mouse chromosome 16.

Animals↗
PubMed2000

Simultaneous analysis of [3H]-thymidine uptake and alpha 1(I) procollagen mRNA expression in systemic sclerosis skin fibroblasts--an in situ hybridization study.

Heterogeneity of DNA synthesis and collagen synthesis has been reported in skin fibroblasts from systemic sclerosis (SSc) patients. The uptake of [3H]-thymidine and expression of alpha 1(I) procollagen mRNA by cultured skin fibroblasts from four normal controls and four SSc patients was analyzed simultaneously. The grains overlying the cytoplasm representing alpha 1(I) procollagen mRNA and overlying the nucleus representing [3H]-thymidine uptake were counted using computer-aided image analysis. The results were analyzed statistically. Procollagen mRNA expression by SSc fibroblasts was significantly greater than by control fibroblasts (P < 0.01). The distribution curve of [3H]-thymidine uptake showed two peaks representing low- and high-uptake cells. Significantly more SSc fibroblasts than control fibroblasts showed high [3H]-thymidine uptake (P < 0.05). The number of SSc fibroblasts expressing low amounts of alpha 1(I) procollagen mRNA was significantly lower than the number of control fibroblasts (P < 0.05). [3H]-thymidine uptake by SSc fibroblasts expressing high amounts of alpha 1(I) procollagen mRNA was significantly lower than by those expressing low amounts (P < 0.05). These results indicate that elevated DNA synthesis and elevated collagen mRNA synthesis in SSc skin fibroblasts are due to different clones with high DNA-synthesizing ability and high collagen-producing ability.

Aged↗
PubMed1990

Chlorate inhibits tyrosine sulfation of human type III procollagen without affecting its secretion or processing.

Sodium chlorate, a potent inhibitor of sulfation reactions, completely inhibits the formation of tyrosine-o-sulfate in type III procollagen in human fibroblasts, when used in concentrations that do not affect the incorporation of radioactive amino acids into protein. The unsulfated type III procollagen is secreted into the medium at a rate comparable, to those of sulfated type III procollagen and type I procollagen, which normally does not undergo sulfation. The enzymatic cleavage of the aminoterminal propeptide of type III procollagen is incomplete in fibroblast cultures, irrespective of the sulfation status of the protein.

Cells, Cultured↗
PubMed1986

Serum type III procollagen peptide as a non-invasive marker of liver damage during infancy and childhood in extrahepatic biliary atresia, idiopathic hepatitis of infancy and alpha 1 antitrypsin deficiency.

To evaluate the role of serum procollagen III peptide as a non-invasive marker of liver damage and prognosis in hepatobiliary disorders of infancy, we have measured its concentration at presentation and serially in 30 infants with extrahepatic biliary atresia, 22 with idiopathic hepatitis of infancy, 10 with alpha 1 antitrypsin deficiency and 105 age-matched controls. Raised procollagen III peptide concentrations occurred in 51% of patients at presentation and 59% at follow up but were not related to the type of liver disease or the severity of liver damage, as assessed either by standard biochemical tests of liver function, serum glycocholic acid, semiquantitative assessment of 11 histopathological features or hepatic prolyl hydroxylase activity. Serum procollagen III peptide concentrations also gave no guide to prognosis. Although the factors determining serum procollagen III peptide concentrations in hepatobiliary disorders of infancy are unknown at the present time, we suggest that changes in growth rate may be of major importance in determining the significance of serum procollagen III peptide concentrations in infants and children.

Biliary Atresia↗
PubMed1989

Hyaluronic acid and type III procollagen peptide in jejunal perfusion fluid as markers of connective tissue turnover.

Hyaluronic acid (hyaluronate, HA) and type III procollagen N-terminal peptide were measured in jejunal perfusion fluid in an attempt to elucidate the turnover of connective tissue components in the small bowel in health and disease. In healthy controls (n = 16) the average concentration of hyaluronic acid in jejunal perfusion fluid was 12.2 +/- 2 micrograms/L (mean +/- SEM); the mean serum concentration was 22 +/- 7 micrograms/L. The type III procollagen N-terminal peptide concentration in jejunal fluid was 0.12 +/- 0.02 micrograms/L; the mean serum concentration was 12 +/- 0.7 micrograms/L. The albumin concentration in perfusion fluid was, on average, 0.04% of the serum values. Patients with celiac disease (n = 7) and Crohn's disease (n = 10) had normal serum levels of HA and type III procollagen N-terminal peptide. The jejunal secretion rate of HA was significantly increased in both disease groups and on average about three times higher than that in controls. The secretion rate of type III procollagen N-terminal peptide was not altered in celiac disease but increased more than three times in Crohn's disease. Habitual alcoholics investigated after alcohol withdrawal also had significantly increased jejunal secretion of HA but not of type III procollagen N-terminal peptide. In contrast, patients with alcoholic liver cirrhosis and similar ethanol intake had normal secretion of both substances. The findings of the study indicate that the secretion of HA into the jejunal lumen in health is considerable, possibly reflecting the rapid turnover of the intestinal mucosa. The enhanced jejunal secretion of HA in patients with celiac disease and Crohn's disease may be indicative of enhanced connective tissue response due to inflammation, but signs compatible with enhanced jejunal synthesis of type III collagen are only found in Crohn's disease. The HA secretion data in alcoholics might reflect (a) the active regeneration of the intestinal mucosa when ethanol is discontinued and (b) a possible role of the liver in this activity.

Adult↗
PubMed1992

Cellular localization of procollagen gene transcripts in inflammatory bowel diseases.

The cellular localization of procollagen types I, III, IV, and V gene transcripts was determined in tissues from 12 patients with either Crohn's disease (CD) or ulcerative colitis (UC) and nine controls by in situ hybridization with 35S-labeled RNA probes. In CD, the signal intensity and number of labeled cells were significantly increased, particularly in deeper intestinal layers. In contrast, the labeled cells in UC were concentrated in the subepithelial intestinal layers, with an overexpression of procollagen III RNA transcripts. Immunohistological stainings for procollagen types I, III, and IV showed a weaker staining in UC than in CD, indicating that increased transcript levels in UC are unrelated to the enhanced collagen protein deposition, although the increase of procollagen messenger RNA levels correlated with the density of the inflammatory infiltrate. It was concluded that both CD and UC show highly increased procollagen RNA transcript levels but differ in collagen deposition. Thus, different posttranscriptional or posttranslational regulatory mechanisms, such as collagen degradation, may account for the observed differences.

Adult↗
PubMed1983

Cortisol decreases the cellular concentration of translatable procollagen mRNA species in cultured human skin fibroblasts.

The effect of cortisol on the cellular concentration of translatable procollagen mRNAs was studied in cultured human skin fibroblasts. Cortisol selectively decreased the amount of procollagen mRNAs, in comparison to the total mRNA activity, when the cells were grown in enriched medium conditions, i.e., with 10% newborn calf serum. The selective decrease was first observed after 6 h exposure to 1 microM cortisol. In depleted medium conditions, i.e., with 2% newborn calf serum, the initial response was a stimulatory one, followed after about 12 h by a decrease in the procollagen mRNA activity. The results suggest that the selective inhibitory effect of cortisol on the cellular concentration of translatable procollagen mRNA species needs an optimal serum concentration. Furthermore, the results give support to the hypothesis that the decrease in the procollagen mRNA concentration after cortisol administration is a secondary response, preceded by the induction of some intracellular regulation system.

Cells, Cultured↗
PubMed1979

Accumulation of procollagen in the degenerative articular cartilage of dogs with osteoarthritis.

Collagen metabolism was studied in degenerative articular cartilage of dogs with spontaneous, early onset osteoarthritis. A fraction of collagen which represented about 1.5% of the total was extracted from cartilage samples with dilute phosphate buffer (pH 7.4) containing 0.2% sodium dodecyl sulfate. Agarose gel filtration in the presence of sodium dodecyl sulfate revealed that extracts of degenerative cartilage had about 24% procollagen whereas extracts of normal samples had only 3%. The isolated procollagen fraction was rechromatographed on agarose columns in the presence of mercaptoethanol. This resulted in the identification of a collagen species which migrated between marker beta and alpha collagen chains. The molecular weight of this collagen was estimated to be 150,000. Based on incorporation of [14C]proline, its ratio of hydroxy[14C]proline to total 14C was 0.32. Procollagen was not found after limited pepsin digestion (pH 3, 4 degrees C, 16 h) of degenerative cartilage samples. Since the total collagen content (microgram hydroxyproline/mg cartilage), hydroxy-[14C]proline/mg cartilage, specific radioactivity of hydroxyproline in the extractable collagen fraction were similar for normal and degenerative cartilage we propose that procollagen accumulated in the degenerative cartilage due to a partial defect in conversion of procollagen to collagen.

Animals↗
PubMed2004

Enhanced procollagen processing in skeletal muscle after a single bout of eccentric loading in humans.

Increases in procollagen processing within skeletal muscle have previously been reported in small animal models only. While indirect measurements in humans have suggested an increase procollagen processing, no intra-skeletal muscle measurements have confirmed these findings. In this study, eight young healthy male subjects performed a single bout of unaccustomed high intensity eccentric exercise on one leg, with the contralateral leg being the control. A significant increase in the muscle interstitial concentration of the N-terminal propeptide of procollagen type I (PINP) was observed (day 0: 1.96 +/- 0.44 ng ml(-1), day 2: 1.94 +/- 0.32 ng ml(-1), day 4: 3.90 +/- 1.03 ng ml(-1), day 8: 7.23 +/- 2.34 ng ml(-1)*, *P < 0.05 vs. basal and control) with no change being noted in the control leg. By day 2 post-exercise, an increase in the histological immunoreactivity of PINP and the N-terminal propeptide of procollagen type III (PIIINP) was also shown in the exercising leg only. Further, from day 2 post-exercise, immunoreactivity for tenascin C and reactive macrophages (CD68+ cells) was seen within the perimysial and endomysial connective tissue of the exercising leg only, indicating a high mechanical load and inflammation. This study shows that following a single bout of high intensity eccentric exercise there is an increase in procollagen processing within skeletal muscle in humans.

Adult↗
PubMed1997

Serum laminin and type III procollagen in chronic hepatitis C. Diagnostic value in the assessment of disease activity and fibrosis.

Laminin P1 (pepsin-resistant fragment of laminin) and aminoterminal peptide of type III procollagen are measurable in serum and are now considered useful serum markers of fibrogenesis and inflammation in chronic liver diseases. However, very few studies thus far have focused on assessing the diagnostic value of these markers in detecting fibrosis and necro-inflammatory activity in chronically diseased liver. The aim of the present study was therefore to investigate the correlations of laminin and type III procollagen with liver histology and to compare their diagnostic value in detecting the degree of liver fibrosis and necro-inflammatory activity in a homogeneous group of 99 patients suffering from chronic hepatitis C, and lacking other factors which can directly affect the serum levels of the two markers. Both these serum markers were measured by radioimmunoassay, employing commercially available kits. The three main aspects of liver pathology, i.e. portal-periportal activity, lobular activity and fibrosis, were histologically evaluated and semiquantitatively expressed by numerical scores. The results of this study show that laminin and type III procollagen were both positively correlated with the histological scores for portal-periportal activity and with those for fibrosis, whereas no significant correlation was observed between each of the two serum markers and the histological scores for lobular activity. The sensitivity and specificity of laminin and type III procollagen in detecting histological aspects of fibrosis and disease activity in liver, computed at various cut-off levels, showed overlapping trends for the two markers; however, the diagnostic value was in general rather low, whatever the cut-off considered. We therefore conclude that the 'static' measurement of both serum laminin and type III procollagen is of limited value for individual diagnosis of liver damage.

Adolescent↗
PubMed1999

Monocyte prostaglandins inhibit procollagen secretion by human vascular smooth muscle cells: implications for plaque stability.

Extracellular matrix remodelling occurs during atherosclerosis dictating the structure of the plaque and thus the resistance to rupture. Monocytes and macrophages are believed to play a role in this remodelling. In the present study, filter-separated co-culture has been used to study the effect of monocytes on procollagen turnover by human vascular smooth muscle cells (VSMC). In this system, freshly isolated human peripheral blood monocytes inhibited procollagen secretion from VSMC without affecting either degradation of procollagen, or DNA synthesis by the VSMC. Insertion of a 12 kDa dialysis membrane between the two cell types and treatment with indomethacin showed that the inhibitory factor was of low molecular weight and was cyclooxygenase-dependent. Pre-incubation of each cell type with indomethacin demonstrated that monocyte, but not VSMC cyclooxygenase was required. Thus, the inhibitory effect on procollagen secretion was due, most likely, to monocyte prostaglandins. Neither inhibition of thromboxane synthetase, nor blocking IL-1 activity, reduced the inhibitory activity. Addition of prostaglandins PGE1, PGE2 and PGF2alpha to VSMC cultures caused a reduction in procollagen secretion which was equivalent to, but was not additive with, the maximal effect achieved by monocytes. Monocytes and macrophages are a major source of prostaglandins and these molecules are likely to play an important role in collagen turnover within lesions.

Arteries↗
PubMed1997

Procollagen production in fresh and cryopreserved aortic valve grafts.

Long-term durability of aortic valve allografts may be enhanced by cellular capacities for regeneration and repair. To evaluate aortic valve graft production of an important structural protein, rat aortic roots were implanted heterotopically into the abdominal aorta of recipient rats. Grafts were either syngeneic or strongly allogeneic, were implanted either fresh or after cryopreservation, and were left in place 2 to 21 days after implantation. A total of 80 aortic valve grafts and the corresponding native aortic valves were examined. The grafts were retrieved and immunocytochemically stained for the presence of procollagen, a precursor to collagen. Regardless of histocompatibility or preservation, grafts exhibited consistent procollagen presence that equaled or exceeded that seen in the corresponding native valves. Positive procollagen staining was predominantly in the aortic wall. The most prominent staining was near the hinge point of the valve leaflets, with no staining in the free portion of the leaflets. Staining with alpha-actin demonstrated vascular smooth muscle in sites remote from the areas positive for procollagen, which suggests that vascular smooth muscle was not responsible for the procollagen production. These findings indicate that cryopreservation is compatible with persistent fibroblast viability and in vivo protein synthesis by both syngeneic and allogeneic aortic valve grafts.

Animals↗
PubMed1997

Abundance of alpha 1(I) and alpha 1(III) procollagen and p21 mRNAs in fibroblasts cultured from fetal and postnatal dermis.

The steady-state abundance of alpha 1(I) and alpha 1(III) procollagen mRNAs, p21Sdi1 mRNA, and beta-actin mRNA was determined in 29 skin fibroblast lines established from fetal, young and old donors. Donor ages ranged from 12 gestational weeks to nonagenarian. Adult donors were members of the Baltimore Longitudinal Study of Aging. The abundance of alpha 1(I) procollagen mRNA was decreased in cell lines from both young and old donors compared with fetal lines. Additionally, one alpha 1(I) transcript observed in the fetal lines was not detected in postnatal lines. The abundance of alpha 1(III) procollagen mRNA was decreased in postnatal lines from old donors compared with fetal lines. The abundance of beta-actin mRNA was lower in postnatal lines from both young and old donors compared to fetal lines. These results suggest that cultures of fetal skin fibroblasts exhibit a greater capacity for synthesis of procollagens and beta-actin than postnatal lines. In contrast, the abundance of p21Sdi1 mRNA was elevated in lines established from postnatal donors. These results are consistent with developmental changes in amounts of procollagen, beta-actin and p21.

Actins↗
PubMed1998

A chemically modified tetracycline inhibits streptozotocin-induced diabetic depression of skin collagen synthesis and steady-state type I procollagen mRNA.

Wasting of connective tissues including skin, bone, and cartilage have been closely associated with elevated matrix metalloproteinase (MMP) activity and depressed collagen content in the streptozotocin (STZ)-induced diabetic rat, while tetracyclines have been reported to normalize total body weight, skin hydroxyproline and collagen content in this model, in part through inhibition of MMPs. In the present study, we report the effect of CMT-1, a chemically modified tetracycline that lacks antimicrobial properties but retains divalent cation binding and MMP inhibitory activity, on diabetic skin collagen synthesis and steady-state levels of procollagen alpha 1(I) mRNA. Male, 4-month old Sprague-Dawley rats received a single injection of 75 mg/kg STZ or citrate vehicle alone and diabetic status was confirmed by positive glucosuria. Some diabetic animals received 10 mg/day of CMT-1 by oral gavage and, 28 days after STZ treatment, body weight, blood glucose values and the in vivo rates of skin collagen production were measured using the pool-expansion technique. Steady-state levels of procollagen alpha 1(I) mRNA were analyzed 21 days after STZ treatment by hybridization of total RNA with a 32P labelled cDNA to rat type I procollagen alpha 1(I) mRNA in a dot-blot assay. STZ treatment was found to significantly depress body weight, skin collagen hydroxyproline content, the in vivo rate of collagen production, and hybridizable levels of type I procollagen alpha 1(I) mRNA. CMT-1 administered daily to STZ-treated rats inhibited the diabetic depression of these parameters but had little or no effect on non-diabetic controls or on STZ-induced hyperglycemia. Thus, in addition to the inhibition of MMP mediated extracellular collagen degradation, these results suggest CMT-1 also acts to inhibit diabetic connective tissue breakdown in STZ-induced diabetes by increasing both steady-state levels of type I procollagen mRNA and collagen synthesis through mechanism(s) that are independent of the antibacterial properties of tetracyclines.

Animals↗
PubMed1985

Immunochemical characterization of type IV procollagen from anterior lens capsule.

Basement membrane collagen from bovine anterior lens capsules (ALC) was isolated by a non-degradative procedure and characterized. The material was obtained by extracting the ALC with 0.5 M acetic acid, passing the extract through a DEAE-cellulose column, collecting and concentrating the unbound fraction. Amino acid and carbohydrate analysis, polyacrylamide gel electrophoresis and rotary shadowing electron microscopy showed the purified extract to have the characteristics of basement membrane procollagen. Examination by rotary shadowing revealed the material to consist of type IV procollagen-like tetramers in various degrees of aggregation. When this purified procollagen was injected into rabbits, antibody of high titer and specificity was obtained. The competitive ELISA was then used to demonstrate lack of reactivity of the antibody with collagen types I, II, III and V and fibronectin. The electroimmunoblot technique was used to demonstrate lack of reactivity with laminin. Competition with collagenase resistant fragments of type IV procollagen representing the carboxyl terminal domain (NCI) and the 7-S domain, as well as with a pepsin-resistant alpha 1 (IV)125K chain was markedly weaker as compared to the native type IV procollagen molecule.

Animals↗
PubMed1987

Production of monoclonal antibodies recognising N-ethylmaleimide during attempted generation of monoclonal antibodies to human type I procollagen.

Mice were immunised for the production of monoclonal antibodies to human procollagen (I) using antigen purified from fibroblast conditioned medium. The procedure for procollagen (I) preparation included the addition of proteinase inhibitors N-ethylmaleimide, phenylmethylsulphonyl fluoride and ethylenediaminetetraacetic acid to prevent damage by proteolytic cleavage. Four of the five monoclonal antibodies subsequently produced were found to recognise the thiol proteinase inhibitor N-ethylmaleimide but not type I procollagen prepared in the absence of N-ethylmaleimide. One of these monoclonal antibodies was examined further and shown to recognise beta-galactosidase after it had been reacted with N-ethylmaleimide. As far as we are aware this is the first time that monoclonal antibodies have been produced which recognise N-ethylmaleimide. Our findings indicate an unexpected reaction between procollagen and N-ethylmaleimide and prompt the suggestion that the use of N-ethylmaleimide in the purification of procollagen and other proteins should be reexamined.

Antibodies, Monoclonal↗
PubMed2002

Osteochondromatosis with high concentration of procollagen II C peptide in joint fluid.

Procollagen II C peptide is used as a joint fluid marker of collagen synthesis by chondrocytes in patients with osteoarthritis. Since osteochondromatosis activates ectopic chondrogenesis in the synovial membrane, procollagen II C peptide is expected to be a good marker of the disease. Procollagen II C peptide can be used to evaluate the condition of the disease metabolically by simply aspirating the joint fluid. We have experienced a case of osteochondromatosis (Miligram's stage 2) with a high concentration of procollagen II C peptide. This case suggests that the concentration of procollagen II C peptide is a good marker of chondrogenesis by osteochondromatosis.

Adult↗