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Significance of serum levels of type I procollagen peptide and intact osteocalcin and bone mineral density in patients with ossification of the posterior longitudinal ligaments.

This study was performed to evaluate the correlation between serum biochemical marker levels of bone metabolism and bone mineral density (BMD) in patients with ossification of the posterior longitudinal ligaments (OPLL). In addition, the efficacy of these markers in the prediction of the progression of OPLL was also examined. In 40 patients with OPLL, and in age- and gender-matched controls (n = 36), the levels of C-terminal extension peptide of type I procollagen (PICP) and intact osteocalcin were quantitated by a sandwich enzyme-linked immunosorbent assay as serum markers of bone formation. BMD of the whole body was measured using dual-energy X-ray absorptiometry. Serum PICP and intact osteocalcin levels were significantly increased in patients with OPLL. There was a significant correlation between serum bone formation marker levels and BMD in both the OPLL and the control groups. Patients with radiological progression of OPLL showed a level higher than the mean + 2 SD of controls in PICP, intact osteocalcin, and BMD. In addition, the levels of serum PICP and intact osteocalcin increased in correspondence with the progression of OPLL without statistical significance. In patients without any growth of OPLL, however, all the parameters were below the mean + 2 SD of controls. Thus, aggravation of bone formation activity was suggested to be closely correlated with the development of OPLL. In addition, serial measurements of these parameters might be useful for estimating the progression of OPLL.

Adult↗

Prediction of bone mass in renal hyperparathyroidism by newly developed bone metabolic markers: evaluation of serum levels of carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen and carboxy-terminal propeptide of type I procollagen.

Serum levels of the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) and the carboxy-terminal propeptide of type I procollagen (PICP) were measured in 95 patients with renal hyperparathyroidism who had undergone a total parathyroidectomy and autotransplantation of a small portion of the resected gland. The results were compared with the serum levels of other bone metabolic markers and bone mineral densities in the distal radius (R-BMD) and lumbar vertebrae (L-BMD), which were measured by dual energy x-ray absorptiometry and converted to the percentage of the mean value of sex- and age-matched healthy controls. The preoperative mean values of ICTP and PICP were 142.4 ng/ml and 187.8 ng/ml, respectively. Although the serum levels of PICP levels exceeded the normal range in 42.1% of the patients, those of ICTP exceeded it in all of them. The serum levels of ICTP correlated positively not only with those of tartrate-resistant acid phosphatase (TRACP), total alkaline phosphatase (ALP), and osteocalcin but also negatively with the values of %R-BMD and %L-BMD and seemed to manifest specifically the disturbance of bone metabolism. On the other hand, the serum levels of PICP correlated with those of ALP and TRACP but not with values of %BMDs. After surgery, the serum levels of ICTP decreased gradually, but those of PICP increased immediately up to peak values at 7 days and then decreased gradually after 14 days, reaching the normal range at 3 months. These changes in the bone metabolic markers seemed to reflect the change in bone metabolism that was converting from bone resorption to bone formation. The percent change in the PICP/ICTP ratio at 7 days correlated significantly with the percent change in R-BMD at 12 months, and it was suggested that postoperative bone gain might be predicted using a combination of postoperative changes in PICP and ICTP.

Absorptiometry, Photon↗

Evaluation of procollagen-III peptide as a marker for veno-occlusive disease after bone marrow transplantation.

Procollagen-III peptide (PIIIP) has been suggested as a marker for hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). Using the RIA-gnost PIIIP assay, we examined frozen plasma samples from three groups of patients. The groups included (A) four patients with clinically proven VOD, (B) nine patients with remarkably uneventful post-BMT courses, and (C) patients with either early complications other than VOD or pulmonary fibrosis in their later course. In group A, PIIIP levels increased parallel to the clinical course, with maximum values of 2.7-5.5 units/ml. In group B, values did not exceed 1.4 units/ml. In group C, higher values were occasionally observed. In one patient with early relapse of a lymphoma PIIIP peaks correlated with episodes of fever and graft versus host disease (GVHD). In another patient mild VOD seems possible retrospectively. The highest levels ( > 15 units/ml) occurred in one patient with ileus. Several patients with interstitial pneumonia (IP), adult respiratory distress syndrome (ARDS), or lung fibrosis showed increases in PIIIP levels corresponding to the clinical course; most of these events occurred later than day 30 after BMT. One patient with severe GVHD of the liver showed a maximum of only 1.4 units/ml. PIIIP elevation correlated with clinical VOD and may help to differentiate it from hepatic GVHD. In the presence of other complications (pulmonary, gastrointestinal), some caution in interpreting the results may be advisable.

Adult↗

The relationship between procollagen-III-peptide and the severity of esophageal varices in children with biliary atresia after Kasai operation.

Biliary atresia (BA) is a common cause of infantile cholestasis. Disease progression leads to intra hepaticfibrosis, and thus to the development of PH and EV. Our objective has been to study the relationship between procollagen-III-peptide (PIIIP) and the severity of EV in children with BA after Kasai operation. Children below 15 years of age (n=29) with BA after a Kasai operation were evaluated for EV by endoscopy. Healthy (n=26) children of the same age and sex distribution who participated in the hepatitis B vaccination program served as the controls. Serum PIIIP was determined by radioimmunoassay. The BA patients were classified on the basis of severity of EV (Paquet's classification) into three groups: group 1 (n=15) had grade 0, group 2 (n=8) grade 1-2, and group 3 (n=6) grade 3-4 EV. In group 3, serum PIIIP (2.9 +/- 1.3 IU/ml) was significantly higher than in group 2 (1.5 +/- 0.4 IU/ml) (P < 0.05). Serum PIIIP levels were increased in group 2 compared with group 1 (1.2 +/- 0.4 IU/ml) and in group 1 compared with the control group (1.2 +/- 0.2 IU/ml), but this difference was not significant. PIIIP levels increased with severity of the EV in the BA patients. Hence, high PIIIP levels may serve as a non invastive indicator of EV developing in postoperative BA patients.

Adolescent↗

Determination of the complete cDNA sequence of rat type II collagen and evaluation of distinct expression patterns of types IIA and IIB procollagen mRNAs during fracture repair in rats.

Elucidating the molecular mechanisms that underlie fracture healing is crucial to understanding and devising strategies for the management of fractures, especially those associated with a pathological condition such as diabetes or old age. Cartilage formation, and therefore the expression of type II collagen by chondrocytes, is a critical step in frac-ture healing. Two forms of type II collagen, IIA and IIB, are known to be produced by alternative splicing of the Alpha(1) (II) procollagen gene. We have followed the patterns of expression of these two forms of type II collagen to determine the nature of chondrocyte recruitment during fracture healing. First, we sequenced the rat collagen type II cDNA to design the primers. Second, using a competitive quantitative reverse transcription-mediated polymerase chain reaction, we provide evidence that (1) there is a basal level of type IIA collagen expression during the early stages of fracture healing; (2) transient but sharp up-regulation of IIA expression occurs concomitant with chondrogenesis and endochondral ossification; and (3) type IIB collagen is the predominant mRNA variant expressed at virtually all times during fracture repair.

Animals↗

[Research on subcellular localization of procollagen proline hydroxylase from chick embryo liver (author's transl)].

Subcellular fractionation by differential centrifugation was used to study protocollagen proline hydroxylase (EC 1.14.11.2) localization from chick embryo liver. The fractions have been characterized by marker enzymes and electron microscopy. By these methods, it was observed that procollagen-proline-hydroxylase is concentrated in the microsomal fraction which is sedimented at 145 000 X g in 250 mM sucrose.

Animals↗

Type III procollagen peptide and PZ-peptidase serum levels in pre-cirrhotic liver diseases.

To obtain a dynamic and non-invasive picture of hepatic fibrosis in pre-cirrhotic liver diseases we measured both the concentration of the N-terminal peptide of procollagen III, as a marker of collagen synthesis, and the activity of PZ-peptidase, an enzyme involved in collagen degradation, in the serum of alcoholic or chronic viral hepatitis patients. Peptide serum levels were similar in chronic persistent hepatitis and controls, but significantly higher in chronic active hepatitis. Chronic persistent hepatitis patients had PZ-peptidase levels higher than controls, but similar to chronic active hepatitis. The increase in collagen synthesis without a parallel increase in collagen degradation seen in chronic active hepatitis could be regarded as a sign of impending cirrhosis, whereas the unbalanced rise in PZ-peptidase observed in chronic persistent hepatitis is consistent with the non-progressive character of this disorder. In alcoholic hepatitis both peptide concentration and PZ-peptidase activity were elevated, thus suggesting that both collagen synthesis and degradation are activated. However, the greater increase in PZ-peptidase than in peptide serum levels seen in some patients seems to indicate a minor tendency to progressive fibrosis or a trend towards resolution. Unlike liver disease patients, normal peptide and PZ-peptidase levels were found in patients with pancreatic fibrosis. Since circulating inhibitors and activators of the PZ-peptidase activity can be excluded, as proved by this study, joint peptide and PZ-peptidase serum measurements would seem to offer a simple reliable non-invasive method for differentiating and monitoring progressive and non-progressive forms of hepatic fibrosis.

Adult↗

Aminoterminal procollagen III peptide elevation in alcoholics who are selenium and vitamin E deficient.

Serum aminoterminal procollagen III peptide (PIIIP) was measured in 36 alcoholic subjects. There was a significant elevation of PIIIP in subjects with proven liver disease (median 17.5 ng/ml, n = 24) compared to those without liver disease (median 4.7 ng/ml, n = 12). Those subjects with raised serum transaminase values (AST) had elevated PIIIP values (median 13.7 ng/ml, n = 22) compared to those with normal transaminase values (median 3.7 ng/ml, n = 14). In those alcoholic subjects who were deficient in both selenium and vitamin E there was a significant elevation (p less than 0.01) of PIIIP values (median 26.4 ng/ml, n = 7) compared to subjects with normal levels (median 7 ng/ml, n = 11). Subjects deficient in selenium alone had PIIIP values in an intermediate range. Selenium and vitamin E, as important free radical scavengers, may protect the liver in alcoholic subjects from oxidative damage leading to hepatic fibrosis.

Aspartate Aminotransferases↗

Serum procollagen III N-terminal peptide and laminin P1 fragment concentrations in alcoholic liver disease and primary biliary cirrhosis.

Procollagen type III N-peptide (PIII NP) and laminin P1 fragment (LP1) have both been proposed as markers of liver fibrosis. In this study we evaluated the diagnostic application of both peptides in alcoholic liver disease and primary biliary cirrhosis. Serum concentrations of the peptides were measured by radioimmunoassay. PIII NP and LP1 levels appeared to be significantly raised in patients with alcoholic and primary biliary cirrhosis. Patients with alcohol abuse without cirrhosis had normal or slightly elevated PIII NP levels, but significantly raised LP1 levels. There was a strong correlation between PIII NP and LP1 concentrations.

Humans↗

Evaluation of serum aminoterminal procollagen type III propeptide as an index of portal hypertension and esophageal varices in chronic liver diseases.

The concentration of the aminoterminal propeptide of type III procollagen (P-III-P) was determined in serum of cubital vein and hepatic vein of patients with various types of chronic liver diseases (n = 111) and correlated with the portal venous pressure and with the degree of esophageal varices. The P-III-P level in all chronic liver diseases was correlated (rS 0.542, p less than 0.001) with the portal venous pressure, but in liver fibrotic subjects (n = 29) this correlation (rS 0.310) was not significant, in liver cirrhosis (n = 30) the respective correlation was found to be weak (rS 0.333, p less than 0.05) and similar to that in patients with unspecified chronic liver diseases (n = 52) (rS 0.425, p less than 0.01). Sensitivity and specificity of P-III-P at a cut-off concentration of 12 ng/ml for portal hypertension (portal vein pressure 5 mm Hg) are 0.93 and 0.42, respectively, the diagnostic efficiency is 0.67. Predictive values at the same cut-off level of P-III-P and an assumed prevalence of portal hypertension of 50% are 0.62 and 0.85 for the positive and negative test result, respectively. The level of P-III-P is not related to the degree of esophageal varices. The mean P-III-P concentration in the hepatic vein was found to be significantly (p less than 0.001) higher (about 35%) than that in the cubital vein. It is concluded that P-III-P is not an useful parameter for diagnosis of portal hypertension and monitoring of portal vein pressure and of the degree of esophageal varices.

Catheterization↗

Procollagen III peptide and fibronectin in alcohol-related chronic liver disease: correlations with morphological features and biochemical tests.

In order to clarify the significance of procollagen III peptide (PIIIP) and fibronectin (FN) blood concentration in alcohol related chronic liver disease (ALD), we have investigated their relationships with histological liver features and biochemical liver tests in 44 ALD patients. PIIIP was measured in serum by radioimmunoassay whereas FN was determined in plasma using an immunonephelometric method. In each liver biopsy, steatosis, portal infiltrate, lobular necro-inflammation, portal fibrosis and lobular fibrosis were semiquantitatively assessed by scoring from 0 to 3. A close correlation of PIIIP was found with morphological features of fibrosis (both of lobular and portal type), but not with necro-inflammation or steatosis. PIIIP was also positively correlated with ALP and GGT and exhibited a good diagnostic value in liver fibrosis. On the contrary, FN did not distinguish between normals and patients and was not correlated with any morphological liver feature or biochemical liver test. We also conclude that serum NP3P effectively reflects liver fibrosis, whereas plasma FN seems not related to any of the main histological aspects of liver damage in ALD.

Adult↗

Aminoterminal propeptide of type III procollagen in cerebrospinal fluid. Variation with age and in childhood leukemia.

Analyses of the aminoterminal propeptide of type III procollagen (PIIINP) in the cerebrospinal fluid (CSF) of 55 children and five young adults without any structural central nervous system (CNS) lesion are reported. The concentration was age-dependent, in that infants and small children had quite high values, whereas the concentration remained relatively constant after the age of 1.5 years. The concentrations of PIIINP in the CSF of 44 children with acute lymphoblastic leukemia (ALL) were prospectively determined at the time of diagnosis and during treatment, since deposition of type III collagen is known to occur during fibroproliferative responses triggered by inflammation. Chemical arachnoiditis is known to be associated with intrathecal methotrexate therapy in children with leukemia. The mean concentration in these children at diagnosis (5.8 micrograms/l +/- SD 2.8 micrograms/l) did not differ from that in age-matched controls (6.7 micrograms/l +/- SD 3.2 micrograms/l). Depending on type of the disease, the children were treated according to two different protocols. PIIINP concentrations were significantly higher during the therapy phases which included intrathecally administered methotrexate (P less than 0.001) than at diagnosis of the disease. Corticosteroid treatments were always associated with a significant decrease in PIIINP concentrations (P less than 0.01 and P less than 0.001 in the two groups, respectively), irrespective of the therapy phase. The results suggest that an increase in PIIINP concentration in the CSF of children with ALL is an indicator of a fibroproliferative response in the arachnoid. Corticosteroids may repress this response and possibly also prevent the development of adhesions in the arachnoid.

Adolescent↗

Role of the measurement of serum procollagen type III N-terminal peptide in the evaluation of liver diseases.

Serum N-terminal procollagen-III peptide (PIIIP) was measured in 151 patients with diverse liver diseases together with other clinical and laboratory data. Patients with cirrhosis had higher serum PIIIP than those without cirrhosis (P < 0.0001). Significant associations were found between PIIIP and many data characteristic of liver diseases, including alcohol markers. Serum PIIIP was also associated with portal hypertension (P = 0.0001), although such association was probably due to the fact that most patients with portal hypertension were cirrhotic patients. The predictive values of PIIIP in portal hypertension were too low to be clinically useful. No one single factor could be identified as responsible for the increase in PIIIP and the data suggest that the mechanism is multifactorial. Measurement of serum PIIIP has a limited clinical value in the evaluation of patients with diverse liver diseases.

Adolescent↗

Comparison between serum levels of bone alkaline phosphatase and the carboxy-terminal propeptide of type I procollagen as markers of bone formation in patients following renal transplantation.

The serum concentrations of the carboxy-terminal propeptide of type I procollagen (PICP) were monitored in 52 serum samples from 13 patients receiving renal transplants and the values compared with bone alkaline phosphatase (BAP) concentrations and intact parathyrin levels. There was a significant correlation between BAP and PICP values in all 52 serum samples examined (r = +0.770; P < 0.0001). Before transplantation BAP (P < 0.0001), but not PICP (P > 0.1), was correlated with intact parathyrin levels. BAP concentrations increased from 7.3 +/- 1.2 micrograms/l (median +/- S.E.M.) before transplantation to 13.3 +/- 1.2 micrograms/l 3 months after transplantation (P < 0.01). There was a concomitant rise in PICP levels from 95 +/- 19 micrograms/l to 166 +/- 27 micrograms/l (P < 0.05). No correlation was found between BAP or PICP levels on the one hand and intact parathyrin concentrations on the other at any time following renal transplantation (P > 0.5). In conclusion, PICP may be a useful parameter for monitoring bone formation following renal transplantation.

Adult↗

Diffusional transport of the aminoterminal propeptide of type III procollagen in the interstitium of the globally ischaemic cat myocardium.

Local repair after acute myocardial infarction appears to be reflected by levels in serum of the aminoterminal propeptide of type III procollagen (serum-PIIINP). Furthermore, serum-PIIINP has recently been reported to provide information on prognosis after acute myocardial infarction. However, no attention has yet been paid to the resistance to diffusion offered by the myocardial interstitium. We determined the diffusion coefficient of PIIINP in the interstitium of the globally ischaemic interstitium of the cat (D'37) by means of a "true transient diffusion' method, and compared with the free diffusion in water (D37). D'37 (in cm2 s-1.10(-5) was 0.0157 +/- 0.0005 (mean +/- SEM) (n = 13), and D37 was 0.0624 +/- 0.0024 (n = 12). The mean diffusive progression during 20 min of the concentration profile of [125I]PIIINP into the tissue was calculated to be 0.19 mm. The D'37 of albumin is practically identical to the D'37 of PIIINP, and the myocardium offers a similar resistance to diffusion of PIIINP and albumin, as expressed from the ratio D37/D'37 of approximately 4 for both molecules. PIIINP has a molecular weight of 42,000 Da, is rod shaped and has an overall negative charge. These characteristics explain the similarity in diffusion coefficients of PIIINP and albumin, which has a molecular weight of 69,000 Da. Albumin is known to pass the membrane of the continuous capillaries of the heart, making it very likely that direct exchange of PIIINP between interstitium and capillary plasma can also occur. During one hour of interstitial diffusion PIIINP will have traversed a distance calculated tp correspond to 15-20 capillaries. Therefore, the results support the concept of serum-PIIINP as a direct marker of events taking place locally in the myocardium following acute myocardial infarction.

Animals↗

Initial expression of type I procollagen in chick cardiac mesenchyme is dependent upon myocardial stimulation.

Formation of the atrioventricular (AV) mesenchyme is a critical step in early heart development. Endothelial cells are activated and transformed into a mesenchymal population that invades the cell-free myocardial basement membrane. This process can be duplicated in collagen gel culture, where it has been established that myocardium or its secretory products activate the endothelium. The purpose of the present study was to determine when these activated endothelial and/or mesenchymal cells start producing type I collagen in situ. These results were compared to those obtained from a culture model of mesenchyme formation. The production of type I collagen was monitored using a monoclonal antibody (M38) that recognizes the carboxy-terminal propeptide of human type I procollagen. The initial expression of the latter within activated AV endothelial and mesenchymal cells in ovo was 48 hr following activation. Prior to this time, only the myocardium was reactive with M38. AV explants of early hearts on collagen gels revealed staining of activated endothelial and mesenchymal cells with M38 after 48 hr in coculture with myocardial tissue. Explants that were prevented from activating (myocardium removed) never expressed the M38 antigen. Similarly, AV endothelial monolayers grown in the presence of myocardial conditioned medium activated and expressed type I collagen after 48 hr in culture, whereas those grown in standard medium did not. These results establish the initial expression of type I collagen within activated AV endothelium and mesenchyme. In addition, the data suggest that the expression of type I collagen within the AV mesenchyme may be dependent on extrinsic influences that induce the AV endothelium to transform into mesenchyme.

Age Factors↗

Immune interferon inhibits collagen synthesis by rheumatoid synovial cells associated with decreased levels of the procollagen mRNAs.

Recombinant immune interferon, (interferon-gamma, IFN-gamma) inhibits types I and III collagen synthesis by rheumatoid synovial fibroblast-like cells in culture. This decrease is associated with a decrease in the levels of types I and III procollagen mRNAs in these cells as measured by dot blot hybridization. In the control synovial cells the level of alpha 2(I) mRNA is disproportionately high compared with that of alpha 1(I) or alpha 1(III) mRNA, and IFN-gamma suppresses the level of alpha 1(I) and alpha 1(III) mRNA to a greater extent than that of alpha 2(I) mRNA. The lymphokine, IFN-gamma, may thus have a role in the regulation of collagen synthesis in inflammatory joint disease and other conditions.

Arthritis, Rheumatoid↗

Growth factor and procollagen type I gene expression in human liver disease.

BACKGROUND/AIMS: Growth factors have been implicated in the pathogenesis of liver fibrosis, a major determinant of the clinical course of chronic liver disease. The aim of this study was to study the relationship of growth factor expression to inflammation and fibrosis in a variety of human liver diseases. METHODS: We studied by in situ hybridization the expression of transforming growth factor (TGF) beta 1, platelet-derived growth factor (PDGF) A and PDGF-B, and procollagen type I (pro-I) messenger RNAs (mRNAs) in liver diseases of various etiologies. RESULTS: Pro-I mRNA was expressed by mesenchymal cells at sites of inflammation and scarring, where TGF-beta 1 immunoreactivity was often found, and by perisinusoidal cells. TGF-beta 1 and PDGF-A mRNAs were expressed mainly by mononuclear cells and proliferating ductular cells. TGF-beta 1 mRNA was also expressed by perisinusoidal cells. PDGF-A gene expression was more common than that of PDGF-B. Pro-I and TGF-beta 1 expression correlated with both ductular proliferation and tissue inflammation, whereas PDGF-A and PDGF-B only correlated with ductular proliferation. CONCLUSIONS: Our data suggest that TGF-beta 1 and PDGF are involved in human liver inflammation and fibrosis. The expression of growth factor mRNAs in proliferating ductular cells may indicate a role for these cells in liver fibrogenesis and may help explain the pathophysiology of conditions such as biliary atresia progressing to fibrosis despite the absence of marked inflammation.

Gene Expression↗