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PubMed2005

TGF-beta1 reverses the effects of matrix anchorage on the gene expression of decorin and procollagen type I in tendon fibroblasts.

Transforming growth factor-beta1 is known for its effect on the production of extracellular matrix in tendons. Elevated levels of transforming growth factor-beta1 have been reported in tendon adhesion and tendinosis, which suggests that transforming growth factor-beta1 plays an important role in matrix disturbances. Tendon adhesion involves excessive collagen deposition, whereas tendinosis is associated with increased proteoglycan deposition. It seems that other factors also may affect matrix deposition and modulate the effects of transforming growth factor-beta1. We assessed whether matrix anchorage to Type I collagen or fibronectin could change the gene expression of matrix proteins in tendon fibroblasts, and studied whether the effects of transforming growth factor-beta1 were altered by matrix anchorage. Human patellar tendon fibroblast cultures were prepared in different cell anchorages, and the cellular responses to transforming growth factor-beta1 were measured as gene expression of procollagen Type I, Type III, decorin, and biglycan by real-time reverse transcriptase-polymerase chain reaction. Fibronectin anchorage significantly increased the messenger ribonucleic acid level of decorin, and the messenger ribonucleic acid level of procollagen Type I was decreased by matrix anchorage to either fibronectin or Type I collagen. Transforming growth factor-beta1 increased the messenger ribonucleic acid level of procollagen Type I in Type I collagen-coated plates, but it suppressed the messenger ribonucleic acid level of decorin in fibronectin-coated plates. These findings suggest that interaction of matrix anchorage and transforming growth factor-beta1 is an important determinant of matrix deposition in healing tendons and the development of matrix disturbances in tendons.

Cells, Cultured↗
PubMed1972

Procollagen: conversion of the precursor to collagen by a neutral protease.

An enzymatic activity (procollagen peptidase), capable of converting the biosynthetic precursor procollagen to collagen at neutral pH, has been identified in rat and chick calvarial bone. Limited proteolysis of procollagen with chymotrypsin resulted in a similar transformation. The activity in bone can be demonstrated in vitro despite inhibition of new collagen synthesis by cycloheximide. Preservation of the collagen precursor in preparations extracted with acetic acid results from inhibition of the enzymatic activity at low pH.

Animals↗
PubMed2003

High concentrations of procollagen propeptides in chronic subdural haematoma and effusion.

Procollagen propeptides increase in the CSF after subarachnoid haemorrhage, reflecting increased collagen synthesis in the arachnoid. We studied the induction of dural collagen synthesis after cerebral trauma by measuring the carboxyterminal propeptide of type I procollagen (PICP) and the aminoterminal propeptide of type III procollagen (PIIINP) in 17 subdural haematoma or effusion fluid samples obtained at operation on days 10-85 after head trauma. The concentration of PICP was 78-fold higher and that of PIIINP 156-fold higher, relative to that in the serum. These results indicate that meningeal trauma is followed by a long lasting increase in dural collagen synthesis, and suggest that enhanced synthesis of the various extracellular matrix components may have a role in the development of chronic subdural haematoma or effusion.

Adult↗
PubMed1996

Immunisation of Chickens with the Aminoterminal Propeptide of Bovine Procollagen Type III (Specificity of egg yolk antibodies and comparison with immunoassays using rabbit and mouse antibodies.

Two chickens were immunised with the aminoterminal propeptide of bovine procollagen type III (PIIINP) purified from bovine fetal skin. Both animals developed antibodies binding to either unmodified or iodinated bovine PIIINP, but only one chicken developed antibodies which recognise PIIINP variants in serum. These antibodies were used to establish RIAs to analyze the specificity of these particular antibodies and to compare their specificity with that of published assays, as well as laboratory assay variants utilizing different rabbit and mouse antibodies. In comparison to most anti-PIIINP polyclonal antisera from rabbits the chicken antibodies do not bind to the Col-1 domain of PIIINP, a characteristic which they share with a monoclonal antibody (MAB 238) produced from a mouse immunized with the same antigen. Like the monoclonal antibody, the chicken antibodies exhibit reactivity against intact serum PIIINP and its high molecular weight variants, most probably pN procollagen type III and procollagen type III. While the monoclonal antibody can only be applied to analyze PIIINP in human sera, the avian antibodies show reactivity to the antigen in both, human and rat sera. The chicken anti PIIINP antibodies described in this study may become a powerful tool to quantitative PIIINP in serum of patients with liver fibrosis and in serum from experimental rat models of fibrogenesis. The fact that both can be analyzed with the same assay, gives, for the first time, the opportunity for a direct comparison of the results from human and rat studies designed to evaluate the action of antifibrotic agents.

Journal Article↗
PubMed1998

[Effect of hypoxia on proliferation and alpha 1 (I) procollagen gene expression by human fetal lung fibroblasts].

OBJECTIVE: The effect of 2% hypoxia on the proliferation and alpha 1(I) procollagen gene expression by human fetal lung fibroblast was studied. METHODS: Cell proliferation was determined by cell counting and nonradioactive cell proliferation assay method. alpha 1(I) procollagen gene expression was detected by Northern blot hybridization analysis. RESULTS: Cell number and 490 nm OD expressing low oxygen values were markedly increased by the 24, 48 and 72 h exposure to 2% hypoxia respectively. An obvious increase of the alpha 1(I) procollagen mRNA expression was detected after 24 h exposure to 2% hypoxia. The increase of gene expression could be inhibited by Ligustrazin (30 micrograms/ml, 10 micrograms/ml). CONCLUSIONS: 2% hypoxia plays an important role in the outcome of wound healing and pulmonary vascular remodeling by affecting the function of human fetal lung fibroblasts.

Cell Division↗
PubMed2001

[Modulation of the activity of human alpha1 (I) procollagen gene promoter by basic fibroblast growth factor (bFGF)].

OBJECTIVE: To investigate the modulating effect of bFGF on the proliferation of human cutaneous fibroblasts and on the activity of human alpha1 (I) procollagen gene promoter. METHODS: Human cutaneous fibroblasts were cultured and subcultured by tissue block culture technique. The influence of different concentrations of bFGF on the proliferation of fibroblasts was determined by ELISA method with BrdU incorporated into fibroblast DNA. Three plasmids containing various lengths of 5prime prime or minute flank sequences of human alpha1 (I) procollagen gene and CAT as reporter gene were constructed and transfected into the fibroblasts by FuGENE transfection reagent. The quantitative expression of the fibroblast CAT was determined by ELISA after treatment with bFGF. RESULTS: After 24 hours of treatment of the fibroblasts by serial concentrations (0.25 ng/ml similar 64.00 ng/ml) of bFGF in DMEM containing 2% (v/v) or 10% (v/v) FCS, the BrdU incorporation into DNA was determined. The proliferating rate of the fibroblasts differed significantly from each other in all the groups (P < 0.05). After the fibroblasts were transfected with the three plasmids and treated thereafter by 4 ng/ml and 16 ng/ml of bFGF for 24 hours, the relative CAT expression values were determined. It indicated that the expression value was evidently different between bFGF processing and control groups (P < 0.05). CONCLUSION: bFGF might inhibit the proliferation of human cutaneous fibroblasts and exert negative regulating effect on the human alpha1 (I) procollagen gene promoter sequence in dose -- dependent pattern.

Cell Division↗
PubMed1999

[Acceleration of wound healing in diabetic rats by PDWHF and its relation with its activity to stimulate procollagen I (alpha 1) gene expression].

OBJECTIVE: The effect of platelet-derived wound healing factor (PDWHF) on wound healing in diabetic rats was studied. METHODS: Forty-four male SD rats were randomly divided into 2 groups. Thirty-two rats of experimental group accepted intraperitoneal injection of alloxan (1.5 mg/10 g body weight). Within one or two days after injection, while the blood sugar of the rats was higher than 180 mg/dl, the animal model of diabetic rat should have been established. Then a dorsal incision was given to every rat. After the addition of PDWHF (the experimental group) or bovine albumin (the control group), the incision was sutured up. Seven, ten and fourteen days after operation, the breaking strength of the wound was measured. On another hand, specimen from the wound was taken for the culture of fibroblasts. When the cultured fibroblasts have been incubated with 10% PDWHF for 4, 8 and 12 hours, the procollagen I (alpha 1) mRNA levels were examined respectively, and compared with those of control. RESULTS: Significant difference in wound breaking strength had been observed between PDWHF-treated incisions and the control on 7, 10 and 14 days after wounding (P < 0.01). Experiment in vitro demonstrated that the procollagen I (alpha 1) mRNA levels in wound fibroblasts incubated with 10% PDWHF for 4, 8 and 12 hours were 0.9, 3.7 and 2.2 folds higher than those in fibroblasts in control. CONCLUSION: It was suggested that direct stimulation of procollagen I (alpha 1) gene expression was one of the ways that PDWHF played its role in accelerating wound healing.

Animals↗
PubMed2005

[Aldosterone stimulates alpha1-(1) procollagen mRNA expression in HSC via activation of ERK1/2 and AP-1].

OBJECTIVE: It has been known that the intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis in livers. Aldosterone (Aldo), the principal effector molecule of the RAAS, exerts local effects on cell growth and fibrogenesis. However, the signal transduction mechanisms underlying the effects of Aldo on hepatic fibrogenesis remain to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying the effects of Aldo on the signal passageway of active protein-1 (AP-1). METHODS: In vitro, HSCs-T6 cell line was treated with Aldo for 10 min, 30 min, 60 min, 120 min and 180 min, and protein expression of Phospho-P42/44 was detected by Western blot. In addition, HSCs-T6 cell line was preincubated for 60 min or not with U0126 (an inhibitor of the MAPK/ERK kinase), and also with antioxidant-N-acetylcysteine (NAC) prior to exposure to Aldo for the indicated times. Protein expression of Phospho-P42/44 was measured by Western blot. DNA biding activity of AP-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of RT-PCR, expression of alpha1(1) procollagen mRNA was detected. RESULTS: Aldo stimulated HSC via extracellular signal-regulated kinase (ERK1/2) pathway. Time course experiments showed that Aldo induced Phospho-P42/44 expression, which was abrogated by U0126, reaching a maximum at 10 minutes, and then declined progressively. NAC inhibited the Phospho-P42/44 expression. EMSA showed that stimulation of HSC by Aldo markedly increased AP-1 DNA binding activity. U0126 markedly reduced AP-1 DNA binding activity induced by Aldo; NAC partly decreased AP-1 activity induced by Aldo. Aldo up-regulated expression of alpha1(1) procollagen mRNA, which was attenuated by U0126 and NAC. CONCLUSION: Stimulation of HSC by Aldo results in activation of AP-1 via ERK1/2 pathway, leading to up-regulation of AP-1 target gene alpha1(1) procollagen mRNA expression.

Aldosterone↗
PubMed1994

Type I procollagen COOH-terminal proteinase enhancer protein: identification, primary structure, and chromosomal localization of the cognate human gene (PCOLCE).

Type I procollagen COOH-terminal proteinase (C-proteinase) enhancer, a glycoprotein that binds to the COOH-terminal propeptide of type I procollagen and enhances procollagen C-proteinase activity, was purified from mouse fibroblast culture media. Partial amino acid sequences obtained from proteolytic fragments were found to have identity with the deduced amino acid sequence of a cDNA clone of unknown function, previously isolated from a mouse astrocyte library. Sequences of mouse enhancer cDNA, obtained in the present study, predict a approximately 50-kDa, 468-amino acid protein that differs from the 43-kDa, 402-amino acid protein predicted by the previously reported astrocyte-derived clone. Human cDNAs encode an enhancer of 449 amino acids. Previous biochemical studies have found the mouse enhancer as a 55-kDa form, which is readily processed to 36- and 34-kDa forms, retaining full C-proteinase enhancing activity and the ability to bind the COOH-terminal propeptide. Data presented here show the 36-kDa form to correspond to the amino-terminal portion of the 55-kDa protein. This is the most conserved region between mouse and human enhancers, comprising two domains with homology to domains found in a number of proteases and proteins with developmental functions. Such domains are thought to mediate interactions between proteins. Mouse enhancer RNA is shown to be at highest levels in collagen-rich tissues, especially tendon. The human enhancer gene, PCOLCE, is localized to 7q21.3-->q22, the same chromosomal region containing the type I collagen alpha 2 chain gene, COL1A2.

Amino Acid Sequence↗
PubMed1994

Further evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VII.

Dermal fibroblasts from a Chinese Ehlers-Danlos syndrome type VII patient synthesized approximately equal amounts of normal pro-alpha 2(I) chains of type I procollagen and abnormal ones with electrophoretic mobility of pN alpha 2(I) chains, in which the amino-propeptide (N-propeptide) was retained. Reverse-transcriptase PCR analysis of the proband's RNA showed outsplicing of the 54 base exon 6 in half of the pro-alpha 2(I) mRNAs. Exon 6 encodes 18 amino acids of the N-telopeptide which contains the procollagen N-proteinase cleavage site and a cross-link precursor lysine. Loss of these sequences would result in failure to cleave the amino-propeptide of pro-alpha 2(I) and the accumulation of pN-alpha 2(I) chains. Nucleotide sequencing analyses of the proband's COL1A2 gene showed the presence of a T to C transition at position +2 of intron 6 in one allele and the proband is heterozygous for the defect. This mutation which destroyed the consensus GT dinucleotide at the 5' splice donor site of the intron is responsible for the loss of exon 6 by exon skipping. Electron microscopic analysis of the patient's dermis showed the presence of abnormal collagen I fibrils of irregular diameter and circularity. This mutation in COL1A2 in an EDS VII patient is the first reported case in the Chinese population and is identical to one reported for another EDS-VII (Libyan) patient. The occurrence of an identical mutation in two probands of different ethnic origin is direct evidence that the mutant genotype is the cause of the EDS VII phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1985

Prolyl hydroxylase production can be uncoupled from the regulation of procollagen synthesis.

Primary avian tendon (PAT) cells increase the production of procollagen from 10-12% to 40-50% of total protein synthesis in response to the addition of ascorbate and an increasing cell density. We now show that prolyl hydroxylase (PH) also increases its activity by greater than five-fold in response to increasing cell density; but unlike procollagen production, this is independent of the presence of ascorbate. The increased activity is a result of greater enzyme production and not a shift in the ratio of inactive to active forms which remains constant at about 10% of the total enzyme proteins. We present the possibility that at low cell density the levels of PH activity could limit production of collagen.

Animals↗
PubMed1996

The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet.

No effective therapy has yet developed for liver fibrosis by directory inhibiting the accumulation of extracellular matrix. The effect of a newly synthesized prolyl4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2, 4-di-carboxylic-di(2-methoxyethyl)amide), was examined using the model of choline-deficient L-amino acid (CDAA) defined diet-induced liver fibrosis in 16-week-old male Wistar rats. HOE 077 at doses up to 200 ppm prevented fibrosis in a dose-dependent manner, as indicated by reduced hydroxyproline content in liver as well as inhibition of increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm reduced expression of type III procollagen alpha 1, messenger RNA (mRNA) in the liver, with a good correlation with serum PIIIP and hydroxyproline content of the liver. Histologically, HOE 077 at 200 ppm also reduced proliferation of myofibroblastlike cells (activated Ito cells). These results indicate that a PH inhibitor can prevent fibrosis by inhibiting not only the hydroxylation of proline but also the activation of Ito cells, which are considered the main collagen-producing cells, resulting in reduced expression of procollagen mRNA.

Amino Acids↗
PubMed2001

The globular domain of the proalpha 1(I) N-propeptide is not required for secretion, processing by procollagen N-proteinase, or fibrillogenesis of type I collagen in mice.

The globular domain in the NH(2)-terminal propeptide (N-propeptide) of the proalpha1(I) chain is largely encoded by exon 2 of the Col1a1 gene and has been implicated in a number of processes that are involved in the biogenesis, maturation, and function of type I collagen. These include intracellular chain association, transcellular transport and secretion, proteolytic processing of the precursor, feedback regulation of synthesis, and control of fibrillogenesis. However, none of these proposed functions has been firmly established. To evaluate the function of this procollagen domain we have used a targeted mutagenesis approach to generate mice that lack exon 2 in the Col1a1 gene. Mouse lines were established on both a mixed 129 OlaHsd/Sv and C57BL/6 background and a pure 129 OlaHsd/Sv background. Adult mice on the mixed background are normal in appearance and are fertile. To the extent that they have been studied, procollagen synthesis, secretion, and proteolytic processing are normal in these mice, and collagen fibrillogenesis is only slightly altered. However, breeding of heterozygous mutant mice on the 129 background generated homozygous mutants at only 64% of the expected frequency. These findings suggest that although the N-propeptide is not essential for collagen biogenesis in mice it may play some essential role during embryonic development.

Alleles↗
PubMed1997

Incomplete processing of type II procollagen by a rat chondrosarcoma cell line.

The Swarm rat chondrosarcoma cell line, RCS-LTC, deposits an extracellular matrix that contains the typical type II, IX, and XI collagen phenotype of hyaline cartilage, but the fibrils appear abnormally thin. By N-terminal sequence analysis, the type II collagen from the matrix was shown to have retained its N-propeptides with no evidence of normal processing to type II collagen. Amplification and sequencing of cDNA prepared from the pro alpha1(II) mRNA of these cells showed a normal N-propeptide cleavage site. Furthermore, the type II N-procollagen could be processed to type II collagen by incubation with culture medium from normal chondrocytes. The findings indicate that the RCS-LTC cell line fails to express an active type II procollagen N-proteinase and, therefore, offers a useful culture system in which to study the role of N-propeptide removal in fibrillogenesis.

Amino Acid Sequence↗
PubMed1995

New prolyl 4-hydroxylase inhibitor reduces procollagen gene expression and enzyme-altered lesions in rat liver cirrhosis.

A choline deficient L-amino acid defined (CDAA) diet led to the development of liver cirrhosis in male Wistar rats after 16 weeks. A new prolyl 4-hydroxylase inhibitor, 2,4-pyridine dicarboxylic acid bis [(2-methoxyethyl amide)] (HOE 077), prevented liver fibrosis in a dose-dependent manner without a reduction in increased serum alanine aminotransferase and aspartate aminotransferase in parallel with a reduction in preneoplastic enzyme-altered lesions stained with anti-glutathione S-transferase placental form antibody. HOE 077 reduced the increase in serum procollagen III peptide (PIIIP) in a dose-dependent manner and in proportion to the reduction in mRNA expression of type III procollagen in the liver of rats fed a CDAA diet.

Alanine Transaminase↗
PubMed1999

Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.

A time course study was carried out to elucidate the mechanisms for antifibrotic effect of pirfenidone (PD). Hamsters were intratracheally (i.t.) instilled with saline (SA) or bleomycin (BL) (7.5 units/kg/5 ml). The animals were fed a diet containing 0.5% PD or the same control diet (CD) without the drug 2 days before and throughout the study. The animals were sacrificed at various times after instillation. The lung hydroxyproline level in BL + CD groups was gradually increased and peaked at 21 days to 181% of the SA + CD control. The BL + PD-treated groups showed a gradual decrease in their lung collagen content, showing a maximum reduction of 40% at day 21. The lung malondialdehyde levels of the BL + CD groups were increased by several-fold of the corresponding SA + CD groups at various times. The lung prolyl hydroxylase (PH) activities in the BL + CD groups were also increased by several-fold of the corresponding SA + CD groups at these time points. The hamsters in the BL + PD showed a gradual decrease in the lung malondialdehyde levels from 10 to 21days compared with their corresponding BL + CD groups. Treatment with PD also reduced the lung PH activities in the BL + PD groups compared with the corresponding BL + CD groups. However, PD failed to manifest any direct inhibitory effect on PH activity in vitro. BL treatment increased the lung procollagen I and III gene expressions in the BL + CD groups by several-fold at varying times compared with the corresponding SA + CD, and treatment with PD in the BL + PD groups significantly down-regulated the BL-induced overexpression of these genes. Studies evaluating the regulation of these genes at the transcriptional level revealed PD significantly reduced the transcription of PC I at 14 days. Our results indicate that the antifibrotic effect of PD was partly due to suppression of the BL-induced inflammatory events and partly due to down-regulation of BL-induced overexpression of lung procollagen I and III genes.

Animals↗
PubMed1983

Enzymes of collagen synthesis and type III procollagen amino-propeptide in serum from Nigerians with chronic endomyocardial fibrosis.

The hallmark of cardiac pathology in chronic African endomyocardial fibrosis is the laying down of excess collagen in the endomyocardium. Preliminary observations on the assay of enzymes of collagen synthesis and type III procollagen aminopropeptide in chronic African endomyocardial fibrosis are reported. Serum immunoreactive prolyl hydroxylase protein was elevated in 4, serum galactosyl-hydroxylysyl glucosyl transferase activity was elevated in 5, and type III procollagen aminopropeptide was also elevated in 5 patients. Cardiac cirrhosis and endomyocardial fibrosis could be responsible for the elevated values in these patients. The relative contribution of fibrosis of the myocardium to these elevated values remains to be clarified.

Adolescent↗
PubMed1995

Significance of the levels of carboxy terminal type II procollagen peptide, chondroitin sulfate isomers, tissue inhibitor of metalloproteinases, and metalloproteinases in osteoarthritis joint fluid.

The joint fluid levels of several molecules that reflect the anabolism and catabolism of cartilage matrix and its inflammation were quantitated in patients with primary osteoarthritis (OA) and traumatic arthritis. The carboxy terminal type II procollagen increased in primary OA and traumatic arthritis joint fluid and was thought to be a good marker of the repair response of chondrocytes. We found that the increase of this molecule in the joint correlated well with body mass index in primary OA and the degree of cartilage erosion caused by joint instability in traumatic arthritis. Chondroitin 6-sulfate, an integral part of human aggrecan, was also high in OA and traumatic arthritis joint fluids, and showed a similar distribution with keratan sulfate in each disease group. Stromelysin-1 and tissue inhibitor of metalloproteinases-1 levels in joint fluid were very high in RA, but levels in patients with OA were low. Carboxy terminal type II procollagen appeared most sensitive in the evaluation of risk factors of OA such as obesity and joint instability, compared to other markers tested.

Chondroitin Sulfates↗