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PubMed1995

Similarities of in situ mRNA expression between gelatinase A (MMP-2) and type I procollagen in human gastrointestinal carcinoma: comparison with granulation tissue reaction.

The mRNA localizations of gelatinase A(MMP-2) and type I carcinoma and non-neoplastic fibrous granulation tissue were compared. By in situ hybridization, gelatinase A was shown to be expressed in fibroblasts not only in cancer stroma but also in the "reactive fibrosis zone," which surrounds the invasive margin of cancer. In most cases, no accentuation of gelatinase A expression was observed in the invasive margin. This localization pattern of gelatinase A was essentially the same as that of type I procollagen. In gastric cancer associated with deep ulceration, gelatinase A was more abundantly expressed in fibroblastic cells in granulation tissue of the ulcer base than in cancer stroma. The same situation was found in non-neoplastic fibrous granulation tissue, in which fibroblasts abundantly expressed mRNAs for both gelatinase A and type I collagen. Scar tissue (old fibrotic lesion) showed diminished expression of mRNAs for both gelatinase A and type I procollagen. The localization patterns suggest another function of gelatinase A in cancer tissue as a turnover enzyme of the extracellular matrix.

Colonic Neoplasms↗
PubMed1988

Aminoterminal propeptide of type III procollagen in methotrexate-induced liver fibrosis and cirrhosis.

Twenty-four psoriatic patients on methotrexate were studied with liver biopsies and serum measurements of aminoterminal propeptide of type III procollagen (PIII NP). All but one of nine patients with serum levels of PIII NP above the normal range had liver fibrosis or cirrhosis and no normal liver biopsies were obtained in this group. In contrast, nine normal liver biopsies and two biopsies with minimal fibrosis were found among the 15 patients with normal serum levels of PIII NP. The study indicates that aminoterminal propeptide of type III procollagen can be utilized as a valuable non-invasive marker of fibrogenesis in the liver. This analysis is not specific for the liver, but it seems that the number of liver biopsies probably can be reduced in psoriatics on methotrexate who have normal levels of PIII NP.

Adult↗
PubMed1994

Etretinate administration reduces serum propeptide of type I procollagen level in patients with psoriasis.

The serum carboxyterminal propeptide of type I procollagen (PICP) level in 26 patients with psoriasis was significantly lower than in control subjects (124 +/- 47 and 224 +/- 78 ng/ml, respectively; P < 0.001). The patients were divided into two groups, those treated with etretinate and untreated patients. PICP levels in the treated group were significantly lower than those in the untreated group (P < 0.001), but there was no difference between the control and untreated groups. In addition, there was a negative correlation between PICP levels and the serum etretinate concentration in treated patients (r = -0.622, P < 0.05). There was no difference between procollagen type III aminoterminal propeptide (PIIIP) levels in patients and controls, nor was there any significant difference between etretinate-treated and untreated patients. In cell culture studies, etretinate dose-dependently (from 10(-9) to 10(-5) M) decreased the PICP concentration in the medium of fibroblasts from both healthy subjects and patients. In osteoblast cell culture, PICP levels were reduced only in a high concentration of etretinate (10(-5) M). However, no change was observed in preadipose cells. Our in vivo and in vitro observations indicated that psoriasis per se did not affect either serum PICP or PIIIP levels, but that etretinate had an inhibitory effect on collagen synthesis by fibroblasts. Hence, the administration of etretinate to psoriatic patients is, at least in part, responsible for the reduction of serum PICP levels in these patients.

Adult↗
PubMed1990

Regulation of alkaline phosphatase and alpha 2(I) procollagen synthesis during early intramembranous bone formation in the rat mandible.

We have studied intramembranous bone formation in the developing rat mandible. In this system discrete developmental stages can be readily distinguished: mesenchymal condensation, osteoid deposition, and mineralization. In mandibles of 14-day rat embryos avascular condensed mesenchymal cells can be discerned in a region lateral to Meckel's cartilage and anterior to the first molar bud. In 18-day embryos primary bone structures with mineral deposition are evident, and at 2 days postnatally the mandible is extensively mineralized. In the developing mandible we investigated the pattern of bone/liver/kidney/placenta (BLKP) alkaline phosphatase (ALP) and alpha 2(I) procollagen expression in the differentiating osteoblasts. The level of ALP activity in loose mesenchymal tissue is close to background levels. In contrast, the condensed mesenchymal cells in 14-day embryos, which will subsequently form bone, display intense ALP activity prior to discernible osteoid or mineral deposition. ALP activity in the condensed mesenchymal cells can be inhibited by levamisole, indicating activity of the BLKP gene product. We could not detect a corresponding increase in transcript level for either ALP or alpha 2(I) in the condensed mesenchyme in 14-day embryo using in situ hybridization, probably due to low message abundance. At 18 days, cells throughout the developing mandible express ALP activity, and intense in situ hybridization to BLKP ALP probes is evident in cells lining the developing bone trabeculae. Alpha 2(I) procollagen transcripts have accumulated in cells of the developing mandibular bone, but are not specifically localized to osteoblastic cells. Our results demonstrate that ALP activity is a very early marker of differentiation of cells of the osteogenic lineage, since a marked increase in ALP enzyme activity is clearly detectable in condensed mesenchymal cells prior to osteoid or mineral deposition. In contrast, Wright and Leblond, using the same model system and immunohistochemistry, could not localize type I collagen to preosteoblastic cells surrounding the developing bone trabeculae, and demonstrated localization of type I collagen to osteoblasts bordering developing trabeculae, indicating a substantial increase in type I collagen expression (at least at the protein level) during preosteoblast to osteoblast differentiation. These results indicate a discrete pattern of regulation for both the ALP and alpha 2(I) genes during osteogenic differentiation, which may involve both transcriptional and posttranscriptional regulation.

Alkaline Phosphatase↗
PubMed1979

Procollagen processing. Limited proteolysis of COOH-terminal extension peptides by a cathepsin-like protease secreted by tendon fibroblasts.

An enzymatic activity, capable of removing the COOH-terminal extensions of type I chick procollagen, has been demonstrated in embryonic chick tendons and in cultured tendon fibroblasts utilizing two new methods of analysis. The protease was purified by a combination of ultrafiltration concanavalin A affinity chromatography and gel filtration. The isolated protein has an apparent Mr of 43,000 by gel filtration and sodium dodecyl sulfate gel electrophoresis. The enzyme shows a major pH optimum at 4.2 and is susceptible to inhibitors such as pepstatin and leupeptin; it therefore seems related to the cathepsins. The possibility that this enzyme plays a role in the limited proteolytic processing of procollagen is discussed.

Animals↗
PubMed1983

Immunochemical properties of the aminopropeptide of procollagen type III.

The precursor-specific aminopropeptide of bovine type III procollagen is a strong immunogen in rabbits, guinea pigs and mice and induces antibodies which do not cross-react with type I procollagen. The antibody response is regulated by immune response genes associated with the major histocompatibility complex. Major antigenic determinants were found in the compact, non-collagenous domain (fragment Col 1) located at the N terminus of the aminopropeptide and were destroyed by reduction of disulfide bonds. Minor antigenic determinants independent of disulfide bonds also exist in fragment Col 1 and could be localized on a distinct tryptic peptide. Fragment Col 1 showed a lower affinity for antibody when compared with the intact aminopropeptide which causes a non-parallel shift in radioimmuno-inhibition profiles. Monovalent antibody fragments showed an average tenfold reduction in affinity constant and failed to distinguish between aminopropeptide and fragment Col 1. This indicates that the stronger binding of bivalent antibody by the triple-stranded aminopropeptide is due to multiple interactions with both antibody binding sites which are lost for a single-stranded antigen (Col 1) or with monovalent antibody fragments.

Animals↗
PubMed1984

Formation of the triple helix of type I procollagen in cellulo. Temperature-dependent kinetics support a model based on cis in equilibrium trans isomerization of peptide bonds.

The kinetics of triple-helix formation in type I procollagen at 37 degrees C in cellulo have been found to agree with predictions from the following model: triple-helix formation is initiated after completion of the synthesis of the procollagen polypeptide chains and after the chains associate to form interchain disulfide bonds within the C-propeptide; triple-helix formation propagates from this single nucleation site toward the N terminus of the molecule, interrupted by the random occurrence of peptide bonds in the cis configuration; cis-trans isomerization controls the rate of triple-helix formation. This model predicts that the activation energy of the rate-limiting process should be strongly positive. However, studies of triple-helix formation in vitro using thermally denatured material have shown only a low, or even negative, dependence of the rate on temperature in the physiological range. Here we report the temperature dependence of the rate of triple-helix formation in cellulo and a novel procedure for analyzing the resulting data to give an estimate of the Arrhenius activation energy of the rate-controlling process. It was found that this rate showed a strong, positive dependence on temperature, as expected, and that the activation energy was in satisfactory agreement with independent direct determinations of this parameter for cis-trans isomerizations. These findings lend further support to the model of triple-helix formation described above.

Animals↗
PubMedDate not supplied

Diagnostic and prognostic value of the determination of the aminopropeptide of type III procollagen in patients with primary liver cancer.

Hepatic fibroplasia seems to play an important role in the course of primary liver cancer (PLC) since, for instance, encapsulated and fibrolamellar hepatocellular carcinomas show a definitely better prognosis. In this study, serum procollagen III amino-terminal peptide (PIIIP) levels, which reflect synthesis and release of procollagen type III, were measured with the aim of assessing hepatic fibrogenesis in PLC patients and determining whether serum PIIIP levels play a diagnostic or prognostic role in PLC. Twenty-five patients with PLC, 74 patients with cirrhosis and 38 healthy volunteers were studied. Serum PIIIP levels were determined by a radioimmunoassay (RIA) method. In PLC patients PIIIP serum levels were significantly higher than those of controls and cirrhotic patients (P less than 0.001 and P less than 0.01 respectively) but an analysis of individual values showed an important overlap between PLC and cirrhosis. No correlation was found between serum PIIIP levels and tumour histology, presence or absence of cirrhosis, Child status, possible aetiology of the disease, indices of hepatocellular inflammation, cholestasis and synthesis, or tumour markers. On the contrary, serum PIIIP levels correlated with tumour gross pattern (z = 3, P less than 0.001) and, inversely, with survival (r = 0.659, P less than 0.01), patients with serum PIIIP over 25 ng/mL showing a significantly worse prognosis. These data confirm that hepatic fibroplasia plays an important, but not yet fully understood, role in the course of PLC. From the clinical point of view, PIIIP determination does not add to the differential diagnosis between PLC and cirrhosis but helps to identify patients with larger liver replacements and worse prognoses.

Biomarkers, Tumor↗
PubMed1986

Type III aminoterminal propeptide of procollagen in some haematological malignancies.

Marrow fibrosis is involved in some haematological malignancies. Either because of sampling errors, variations of focal distribution of fibrosis or the discomfort for patients of bone biopsies, conventional histology appears to be unsuitable for the follow-up of myelofibrosis. During collagen synthesis by marrow fibroblasts, the aminoterminal propeptide is removed from procollagen III and released in the serum. Thus, a sensitive radioimmunoassay of type III aminoterminal propeptide of procollagen (PC III) has been tested in myeloproliferative and lymphoproliferative disorders with a marked bone marrow fibrosis. In polycythaemia vera, PC III level was significantly increased as compared to controls and was related to marrow fibrosis of grade I. The more increased PC III values were observed in spent polycythaemia cases initially treated by phlebotomy alone. Follow-up showed a transformation into myeloid metaplasia. In contrast, PC III remained stable in patients treated with radiophosphorus 32P or hydroxyurea who did not transform. In myeloid metaplasia, results of PC III were significantly higher than in controls or polycythaemia vera cases. Myelofibrosis of recent onset (less than 2 years) gave higher values than chronic myelofibrosis. Increased PC III values were also emphasized in chronic myelocytic leukaemia, and in a few cases of refractory anaemia with excess of blasts, hairy cell leukaemia and chronic lymphocytic leukaemia.

Bone Diseases↗
PubMed1997

Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide, osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens.

The main difference between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is the presence of lytic bone destructions in the latter. About 20% of MGUS patients develop MM, and histomorphometric studies have shown disturbed bone turnover rates in some of these patients. This study was performed in order to evaluate whether serum analyses of the C-terminal telopeptide of type I collagen (ICTP), as a reflector of bone degradation, and of osteocalcin, bone-specific alkaline phosphatase (bAP) and the C-terminal propeptide of type I procollagen (PICP), as markers of bone formation, might give information on disturbances of bone metabolism in MGUS. Furthermore, serum N-terminal propeptide of procollagen III (PIIINP) might give information on disturbances in collagen III metabolism in the bone marrow. In the 35 patients examined, serum ICTP was elevated in 12 patients (34%), serum PIIINP elevated in 6 patients (17%), serum osteocalcin elevated in 11 patients (31%), serum bAP elevated in 6 patients (17%), and serum PICP elevated in 4 patients (11%). Serum ICTP correlated significantly with PIIINP (r = 0.72, p < 0.001), and with serum osteocalcin (r = 0.57, p < 0.001) and serum bAP (r = 0.51, p = 0.002). These findings indicate disturbances of bone turnover and affected collagen metabolism in some MGUS patients. Follow-up observation may reveal any prognostic value of these findings.

Aged↗
PubMed1992

Fetal antigen 2: an amniotic protein identified as the aminopropeptide of the alpha 1 chain of human procollagen type I.

Fetal antigen (FA2) was purified from second trimester human amniotic fluid by immunospecific chromatography, gel filtration and reversed-phase chromatography. Gel filtration revealed two molecular forms of FA2 eluting at volumes corresponding to an M(r) of approximately 100 kDa and 30 kDa. SDS-PAGE analysis gave an M(r) = 27 kDa under reducing and non-reducing conditions for both forms, whereas the exact M(r) determined by mass spectrometry was 14,343 +/- 3 Da. FA2 was N-terminally blocked and after tryptic digestion the amino acid composition and sequences of the peptides showed identity with the aminopropeptide of the alpha 1 chain of human procollagen type I as determined by nucleotide sequences. After oxidative procedures normally employed for radio-iodination (iodogen and chloramine-T), FA2 lost its immunoreactivity. An antigen which cross-reacted with polyclonal rabbit anti-human FA2 was demonstrated in fetal calf serum. Gel filtration with analysis of fractions by inhibition ELISA showed that the bovine homologue was present in the same molecular forms as those in human amniotic fluid, and immunohistochemical analysis with anti-human FA2 showed that its distribution in bovine skin was identical to that of FA2 in human skin. FA2 is a circulating form of the aminopropeptide of the alpha 1 chain of procollagen type I, and this is the first description of its isolation and structural characterization in humans.

Amino Acid Sequence↗
PubMed1996

Bone morphogenetic protein-1: the type I procollagen C-proteinase.

Bone morphogenetic proteins (BMPs) are bone-derived factors capable of inducing ectopic bone formation. Unlike other BMPs, BMP-1 is not like transforming growth factor-beta (TGF-beta), but it is the prototype of a family of putative proteases implicated in pattern formation during development in diverse organisms. Although some members of this group, such as Drosophila tolloid (TLD), are postulated to activate TGF-beta-like proteins, actual substrates are unknown. Procollagen C-proteinase (PCP) cleaves the COOH-propeptides of procollagens I, II, and III to yield the major fibrous components of vertebrate extracellular matrix. Here it is shown that BMP-1 and PCP are identical. This demonstration of enzymatic activity for a BMP-1/TLD-like protein links an enzyme involved in matrix deposition to genes involved in pattern formation.

Amino Acid Sequence↗
PubMed1991

Diagnostic value of measurement of serum type I procollagen carboxy terminal peptides in patients with scirrhous carcinoma of the stomach.

We have evaluated the radioimmunoassay for type I procollagen carboxy terminal peptide (type I C-peptide), which is liberated from type I procollagen during its conversion to collagen, in the serodiagnosis of scirrhous carcinoma of the stomach. The mean (SD) serum concentration of type I C-peptide in 39 normal subjects was 41.7 (19.7) ng/ml. The mean serum values and the positive ratio of type I C-peptide in 11 patients with stages II and III scirrhous carcinoma of the stomach were 91.2 (41.9) ng/ml and 54.5%, respectively. In 10 patients with other types of gastric carcinoma, the mean type I C-peptide values were not significantly different from the normal value. Serum type I C-peptide values reflected the clinical course of scirrhous gastric carcinoma in five patients who underwent either operation or chemotherapy. The measurement of serum type I C-peptide concentrations could provide a useful way of diagnosing and monitoring scirrhous carcinoma of the stomach.

Adenocarcinoma, Scirrhous↗
PubMed2002

Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis.

BACKGROUND: The trisubstituted methylxanthine derivative pentoxifylline inhibits hepatic stellate cell proliferation and collagen synthesis in vitro. The antifibrotic effect of pentoxifylline in a suitable in vivo model of chronic liver fibrogenesis remains to be tested. METHODS: Groups of adult rats (n=20-23) received oral pentoxifylline at a dose of 8 mg/kg/day from week 1 to week 6, and 16 mg/kg/day from week 1 to week 6 or week 4 to week 6 after complete bile duct occlusion. Animals who underwent sham operation that received 16 mg/kg/day pentoxifylline and untreated rats with bile duct occlusion alone served as controls. After six weeks, animals were sacrificed and parameters of fibrogenesis determined. RESULTS: Bile duct occlusion caused portal cirrhosis with a 10-fold increased hepatic collagen content in the absence of inflammation or necrosis. This was accompanied by an 11-fold elevated serum aminoterminal procollagen III peptide (PIIINP). The drug induced a dramatic eightfold downregulation of procollagen I mRNA, and suppression of the fibrogenic factors transforming growth factor beta1 and connective tissue growth factor by 60-70%. However, profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was increased twofold, resulting in only a moderate decrease in liver collagen, fibrosis score, and PIIINP. CONCLUSIONS: We conclude that targeting pentoxifylline to the fibrogenic cells, thereby avoiding upregulation of TIMP-1, could become a potent antifibrogenic tool in chronic liver disease.

Administration, Oral↗
PubMed1997

Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy.

OBJECTIVE: To identify new prognostic indicators in idiopathic dilated cardiomyopathy (DCM) and secondary cardiomyopathy. DESIGN AND PATIENTS: Serum concentrations of aminoterminal propeptides of type III procollagen and the 7S domain of type IV collagen (7S collagen)--which have recently been used as indicators of collagen matrix turnover in other diseases--and of cardiac troponin T were measured in 17 consecutive patients with DCM and in four patients with secondary cardiomyopathy (one associated with hyperthyroidism, two with chronic renal failure, one with amyloidosis), confirmed by endomyocardial biopsy. The correlation of these variables with short term prognosis was then assessed prospectively. RESULTS: 11 of the patients were positive for type III procollagen, 7S collagen, or troponin T even though their creatine kinase concentrations were within the normal range. These patients had a poor short term prognosis (p < 0.001). CONCLUSIONS: Within the DCM and secondary cardiomyopathy groups, there was a subgroup of patients with raised concentrations of serum collagen and troponin T, for whom short term prognosis was poor. Although it is unclear whether these serum peptide levels reflect ongoing myocyte degeneration and interstitial fibrosis, they may serve as useful new prognostic indicators for cardiomyopathy.

Adult↗
PubMed1994

Type 1 procollagen as a marker of severity of scarring after sternotomy: effects of topical corticosteroids.

AIMS: To determine whether the abundance of newly formed collagen in healing surgical wounds correlated with scar severity, and whether topical application of steroid cream reduced new collagen formation in patients who have undergone median sternotomy. METHODS: Thirty three patients six weeks after sternotomy, and 12 controls were studied. Scars were photographed, and biopsy specimens from scars at sites treated or untreated with topical corticosteroids (clobetasol proprionate 0.5%) were examined using immunohistochemical staining for type 1 procollagen (PCP 1) and transforming growth factor beta (TGF-beta), and in situ hybridisation for type 1 procollagen messenger RNA (mRNA). RESULTS: The degree of hypertrophy of the scar and the abundance of PCP 1 immunostaining were ranked independently, blind, and a correlation between these two variables was observed (r = 0.604, p < 0.001). The PCP 1 immunostaining was accompanied by a great abundance of PCP 1 mRNA and only a slight increase in TGF-beta immunostaining, when compared with normal skin or mature scars. Following the application of topical corticosteroids, for either 48 hours or twice daily for seven days, there was no reduction in PCP 1 immunostaining nor the abundance of PCP 1 mRNA. CONCLUSIONS: These data suggest that the extent of new collagen formation as assessed by PCP 1 immunohistochemistry may be a useful marker of the exuberance of the scarring process following sternotomy, and that topical corticosteroids are ineffective in reducing this component of the fibrotic response.

Base Sequence↗
PubMed1990

The clinical features of osteogenesis imperfecta resulting from a non-functional carboxy terminal pro alpha 1(I) propeptide of type I procollagen and a severe deficiency of normal type I collagen in tissues.

The features of a baby with lethal perinatal osteogenesis imperfecta (OI II), owing to a frameshift mutation that resulted in the production of a truncated and functionless carboxy terminal propeptide of the pro alpha 1(I) chain of type I procollagen, were studied. The baby (OI26) was heterozygous for an insertion of a single uridine nucleotide after base pair 4088 of the prepro alpha 1(I) mRNA of type I procollagen. Only normal type I collagen was incorporated into the extracellular matrix of bone and dermis resulting in a type I collagen content of about 20% of control tissues. The baby was born at 35 weeks' gestation and died shortly afterwards. He was small and had the radiographical features most like those of OI IIB. The skeleton was poorly ossified. The ribs were discontinuously beaded and the femora were broad with multiple healed fractures of the diaphyses and metaphyses. Other long bones had broad metaphyses with overmodelled diaphyses. The calvarium contained many hundreds of wormian bones. Histological examination showed grossly deficient endochondral and intramembranous ossification. The bone was of a woven type without evidence of lamellar bone or Haversian systems and the osteoblasts did not mature into osteocytes. The cortex of the femur contained Haversian canals but they were surrounded by loose collagen fibres and a mosaic pattern of woven bone and islands of cartilage. We propose that OI IIB can be sub-classified into two groups, one with helical mutations and both normal and mutant type I collagen in the tissues, and the other with carboxy terminal propeptide mutations and a severe type I collagen deficiency, but without mutant collagen in the tissues.

Bone and Bones↗
PubMed1996

Arachnoid cyst and chronic subdural haematoma in a child with osteogenesis imperfecta type III resulting from the substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen.

The features of a child with osteogenesis imperfecta type III (OI III) resulting from the heterozygous substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen were studied. He was born at term with the clinical features of severe OI, including deep grey-blue sclerae. He had severe osteopenia and all long bones were smaller than normal with cortical thinning, metaphyseal expansion, poor metaphyseal modelling, and multiple fractures. However, the vertebrae, pelvis, and shoulder girdle were of normal shape and there were few rib fractures. Histological examination of the calvarium and tibial shaft showed woven bone without lamellar bone or Haversian systems. The shafts of the long bones were widened owing to repeated fractures. Progressive enlargement of the calvarium occurred between 3 and 4.5 months of age owing to bilateral chronic subdural haematomata and a large arachnoid cyst in the Sylvian fissure. The cyst was probably developmental in origin while the subdural collections were probably the result of perinatal skull trauma. The cyst and the subdural collections resolved following drainage but ventricular dilatation with normal cerebrospinal fluid pressure followed. The proband is the first reported case of OI with a glycine substitution by alanine in the pro alpha 2(I) chain of type I procollagen.

Adult↗