Biomedical subjects

Juha Risteli

Publications and source records attributed to Juha Risteli.

35 records · Page 2Linked to original sources

PubMed2004

Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure.

Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal women with early breast cancer. The aim of the present study was to investigate the effect of intravenous intermittent clodronate during adjuvant chemotherapy in prevention of this rapid bone loss. 45 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, all women were randomly allocated to receive either seven cycles of intravenous clodronate infusions (1500 mg each) parallel to the chemotherapy or no further therapy. The mean bone loss in the lumbar spine at 6 months was -0.5% in the clodronate group and -1.4% in the control group (p = 0.22) and, at 12 months, -3.9% and -3.6%, respectively (p = 0.62). Type I collagen metabolite PINP levels at six months were significantly lower in the clodronate group than in the control group: 22.6 microg/l (range 15.7-55.8 microg/l) and 44.0 microg/l (range 12.5-91.9 microg/l), respectively (p = 0.0001). At 12 months, no difference between the PINP levels in clodronate and control groups were seen. In conclusion, in this small study a short-term intermittent intravenous clodronate treatment did not seem to prevent clinically significantly the bone loss related to chemotherapy-induced ovarian failure in premenopausal women with early stage breast cancer, even though a significant reduction of a biochemical marker of bone turnover (PINP) was seen during the therapy.

Adult↗

PubMed2004

A thyroid hormone analogue, triiodothyroacetic acid, corrects corticosteroid-downregulated collagen synthesis.

The aim of this study was to compare the change in collagen synthesis between topical treatments with two doses of triiodothyroacetic acid (TRIAC), a thyroid hormone analogue, and placebo, after pretreatment with topical betamethasone 17-valerate (BM). Eighteen healthy volunteers were pretreated with BM on abdominal skin for 3 days, and were then treated for 14 days with a cream containing TRIAC (0.03% or 0.1%) or a placebo cream. Collagen production was assessed by quantifying the amino terminal propeptides of human type I and type III procollagen (PINP and PIIINP) in fluids from suction-induced blisters on the treated skin. Three days of treatment with BM led to an average reduction of PINP of 70% and of PIIINP of 50%. Seven days after treatment, the median increase in PINP was 230% (p = 0.03) in the Triac 0.03% group, 148% (p = 0.2) in the TRIAC 0.1% and 5% in the placebo group. The median increase in PINP in the skin area from the start of treatment to the end of treatment was 521% (p = 0.06) in the TRIAC 0.03% group, 339% (p = 0.2) in the TRIAC 0.1% group, and 55% in the placebo group (the p values are related to baseline). Seven days after treatment, the median increase in PIIINP was 24% (p = 0.6) in the Triac 0.03% group, 23% (p = 0.6) in the TRIAC 0.1% group, and -12% in the placebo group. The median increase in PIIINP in the skin area from the start of treatment to the end of treatment was 137% (p = 0.7) in the TRIAC 0.03% group, 230% (p = 0.9) in the TRIAC 0.1% group and 58% in the placebo group (the p values are related to baseline). Histologic examinations of sections from punch biopsies taken at the end of the treatment showed more thickened collagen fibers and increased density of PINP-producing dermal fibroblasts in the TRIAC groups compared to the placebo group. The result suggests a potential role for TRIAC-containing cream concomitant with anti-inflammatory topical treatment with potent glucocorticoids to prevent their suppressive activity on dermal collagen production.

Adrenal Cortex Hormones↗

PubMed2004

The production of collagen and the activity of mast-cell chymase increase in human skin after irradiation therapy.

Fibrosis is a common complication of radiotherapy. The pathogenesis of radiation-induced fibrosis is not known in detail. There is increasing evidence to suggest that mast cells contribute to various fibrotic conditions. Several mast-cell mediators have been proposed to have a role in fibrogenesis. Tryptase and chymase, the predominant proteins in mast cells, have been shown to induce fibroblast proliferation and collagen synthesis in vitro. In order to explore the role of mast cells in irradiation-induced fibrosis, we analyzed skin biopsies and suction blister fluid (SBF) samples from the lesional and healthy-looking skin of 10 patients who had been treated for breast cancer with surgery and radiotherapy. The biopsies were analyzed histochemically for mast-cell tryptase, chymase, kit receptor, and tumor necrosis factor-alpha. Skin collagen synthesis was assessed by determining the levels of type I and III procollagen amino-terminal propeptides (PINP and PIIINP) in SBF and using immunohistochemical staining for PINP. Immunohistochemical stainings for prolyl-4-hydroxylase reflecting collagen synthesis and chymase immunoreactivity in irradiated and control skin were also performed. The mean level of procollagen propeptides in SBF, which reflects actual skin collagen synthesis in vivo, was markedly increased in irradiated skin compared to corresponding healthy control skin areas. The mean number of PINP-positive fibroblasts was also significantly increased in the upper dermis of radiotherapy-treated skin. The number of cells positive for tryptase, chymase and kit receptor was markedly increased in irradiated skin. In addition, using double-staining techniques, it was possible to demonstrate that in some areas of the dermis, tryptase-positive mast cells and fibroblasts are closely associated. These findings suggest a possible role of mast cells in enhanced skin collagen synthesis and fibrosis induced by radiotherapy.

Adult↗

PubMed2003

Osteoblast recruitment from stem cells does not decrease by age at late adulthood.

This study was aimed to characterize the ability of human bone marrow mesenchymal stem cells (MSC) to differentiate into osteoblasts in vitro. Twenty-three women and 20 men at late adulthood (52-92 years of age) were selected for the study. MSCs were isolated and cultured in vitro and alkaline phosphatase (ALP) activity, secretion of amino-terminal propeptide of type I procollagen (PINP), type III procollagen (PIIINP) and osteocalcin were analyzed. Matrix mineralization was analyzed by the von Kossa staining and by calcium quantification. We found that the ALP and PINP levels compared with control increased to 2.8- and 2.9-fold, respectively, when cells were cultured for three weeks. ALP activity, PINP and calcium deposition in response to dexamethasone treatment increased by age in women and was unchanged in men. Overall our data suggests that the osteogenic potential of MSCs does not decrease by age in either women or men at late adulthood.

Age Factors↗

PubMed2003

Atrial natriuretic peptide, B-type natriuretic peptide, and serum collagen markers after acute myocardial infarction.

Experimental data suggest that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act locally as antifibrotic factors in heart. We investigated the interrelationships of natriuretic peptides and collagen markers in 93 patients receiving thrombolytic treatment for their first acute myocardial infarction (AMI). Collagen formation following AMI, evaluated as serum levels of amino terminal propeptide of type III procollagen, correlated with NH(2)-terminal proANP (r = 0.45, P < 0.001), BNP (r = 0.55, P < 0.001) and NH(2)-terminal proBNP (r = 0.50, P < 0.01) on day 4 after thrombolysis. Levels of intact amino terminal propeptide of type I procollagen decreased by 34% (P < 0.001), and levels of carboxy terminal cross-linked telopeptide of type I collagen (ICTP) increased by 65% (P < 0.001). ICTP levels correlated with NH(2)-terminal proBNP (r = 0.25, P < 0.05) and BNP (r = 0.28, P < 0.05) on day 4. Our results suggest that ANP and BNP may act as regulators of collagen scar formation and left ventricular remodeling after AMI in humans. Furthermore, degradation of type I collagen is increased after AMI and may be regulated by BNP.

Atrial Natriuretic Factor↗

PubMed2003

Discrepant expression of carboxy- and aminoterminal propeptides of type I procollagen predicts poor clinical outcome in epithelial ovarian cancer.

OBJECTIVE: The metabolism and prognostic value of serum concentrations of the aminoterminal (PINP) and carboxyterminal (PICP) propeptides of type I collagen and the PICP:PINP ratio in relation to the carboxyterminal telopeptide of type I collagen (ICTP) in ovarian cancer were evaluated. METHODS: Fifty patients with epithelial ovarian cancer were evaluated with serial measurements of serum concentrations of PICP, PINP, and ICTP before the operation and at 3-month intervals during the first year after the operation. For statistical analysis the patients were divided into two groups according to clinical outcome (alive vs dead) and clinical behavior (fast progression vs others). RESULTS: The serum PINP concentration before the operation was increased and the PICP/PINP ratio was lowered in patients with poor prognosis (PP) compared to those with good prognosis (GP) and in patients with fast progression compared to others. The serum PICP concentration did not differ between the groups. The circulating ICTP concentration was significantly higher in the PP-group than in the GP group. In Kaplan-Meier analysis the PICP:PINP ratio divided the PP and GP patients (P = 0.0004). In multivariate regression analysis, the independent prognostic variables were clinical stage (P = 0.014, 95% confidence interval (CI) 1.31-11.19) and preoperative serum ICTP concentration (P = 0.048, CI 1.01-5.91). When serum ICTP concentration was excluded from the equation, the PICP:PINP ratio (P = 0.012, CI 1.29-7.83), together with clinical stage (P = 0.013, CI 1.31-10.37), was found to be an independent prognostic variable. When the early and advanced stage patients were analyzed separately, the PICP:PINP ratio was a significant prognostic variable in multivariate analysis in early stage patients and in advanced stages during the first 4 years of follow-up. CONCLUSIONS: A low PICP:PINP ratio was associated with fast progression and poor clinical outcome in ovarian cancer. Evaluation of the PICP:PINP ratio together with ICTP may be valuable in predicting the clinical outcome of ovarian cancer.

Adult↗

PubMed2003

Interleukin-6 and tumor necrosis factor alpha in relation to myocardial infarct size and collagen formation.

BACKGROUND: Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels increase after acute myocardial infarction (AMI) in humans. Experimental data suggest that these cytokines regulate the initiation of scar formation after AMI. We investigated the interrelationships of IL-6 and TNF-alpha, tissue injury, infarct size, cardiac function, and collagen formation in humans. METHODS: Serum and plasma samples were taken on 93 patients receiving thrombolytic treatment for their first AMI. Collagen formation was evaluated by measuring concentrations of serum aminoterminal propeptide of type III procollagen (PIIINP). RESULTS: IL-6 levels increased by 44% (P<.001) and peaked at 24 hours. Peak IL-6 levels correlated positively with area under the curve of creatine kinase MB mass (r=.31, P<.01), peak troponin T level (r=.34, P<.005), and PIIINP measured at discharge (r=.46, P<.001). There were no changes in TNF-alpha levels, and patients with left ventricular dysfunction (EF<40%) had similar TNF-alpha levels as those with preserved left ventricular function. CONCLUSIONS: IL-6 may regulate collagen formation and thus remodeling of the left ventricle after AMI. In addition, TNF-alpha measurement is useless in the assessment of infarct size or left ventricular function during the immediate post-infarction period.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2003

Assay for cross-linked carboxyterminal telopeptide of type I collagen (ICTP) unlike CrossLaps assay reflects increased pathological degradation of type I collagen in rheumatoid arthritis.

We compared the ability of assay for cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and CrossLaps assay to reflect increased pathological degradation of type I collagen in serum and synovial fluid samples of patients with rheumatoid arthritis (RA; n = 40). ICTP and CrossLaps concentrations were correlated with each other and with markers of collagen synthesis (PINP and PIIINP, amino terminal propeptides of type I and type III procollagens, respectively) and with markers of inflammation, i.e., C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Serum ICTP was increased in half of the RA patients, whereas CrossLaps assays were increased only occasionally. Serum ICTP correlated with the other markers of collagen metabolism as well as with CRP and ESR. Serum CrossLaps correlated only with PINP and ICTP, but not with serum PIIINP, CRP or ESR. Two patients had false-positive reactions in the CrossLaps assay due to the rheumatoid factor. The ICTP and CrossLaps antigens were clearly separate peaks in gel filtration analysis. The CrossLaps assay is able to detect the same ICTP antigen, but not vice versa. The ICTP assay reflects increased matrix metalloproteinase-mediated collagen degradation in joints in RA. In contrast, the physiological cathepsin K-mediated bone resorption measured by the CrossLaps assay was only occasionally increased.

Adult↗

PubMed2003

Effect of cyclical intermittent etidronate therapy on circulating osteoprotegerin levels in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the role of serum osteoprotegerin (OPG) as a biochemical marker for disease activity assessment and drug monitoring in patients with rheumatoid arthritis (RA) treated with cyclical etidronate. DESIGN: Forty patients (35 women and 5 men) with RA of <5 years duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with anti-rheumatic therapy or anti-rheumatic therapy alone (without etidronate) in a 2-year, open-label protocol. METHODS: Radiographs of hands and feet and serum samples for the determination of OPG, amino terminal propeptide (PINP), cross-linked C-telopeptide (ICTP) and amino terminal telopeptid of type I collagen were obtained at baseline and at 24 months. RESULTS: Etidronate treatment had no effect on circulating OPG levels, although the significant decline in PINP and ICTP (P=0.001 and P=0.04 respectively) reflected the efficacy of the anti-resorptive therapy. At baseline and at study termination, serum OPG correlated significantly with age (r=0.45; P=0.003 and r=0.56; P=0.0002 respectively). OPG was not related to biochemical markers of bone metabolism, indices of disease activity or radiographic disease progression. At baseline, the mean serum OPG was higher in patients receiving 5-10 mg/day prednisone (82.8+/-4.0 pg/ml, n=16) compared with those receiving <5 mg/day or with no prednisone (69.7+/-4.7 pg/ml, n=23) (P=0.05). CONCLUSIONS: Our results suggested that serum OPG measurement, perhaps because of the complexity of the regulation of the OPG, may be difficult to utilize in the evaluation of anti-resorptive therapy. Moreover, low dose corticosteroid-associated osteoporosis is probably not mediated by inhibition of OPG.

Adult↗

PubMed2003

Two year randomized controlled trial of etidronate in rheumatoid arthritis: changes in serum aminoterminal telopeptides correlate with radiographic progression of disease.

OBJECTIVE: To investigate the effect of intermittent cyclical etidronate treatment on radiographic progression, bone collagen markers, and clinical disease activity in patients with rheumatoid arthritis (RA). METHODS: Forty patients with RA of less than 5 years' duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with antirheumatic therapy or antirheumatic therapy alone (without etidronate) in a 2 year open-label protocol. Radiographs of hands and feet and serum samples for determination of aminoterminal propeptide (PINP), crosslinked C-telopeptide (ICTP), and aminoterminal telopeptides (NTx) of type I collagen were obtained at baseline and at 24 months. RESULTS: There was significant and similar worsening of the radiologic scores in both treatment groups. Both PINP, a marker of bone formation, and ICTP, an indicator of collagen degradation, declined in the etidronate group compared to the control group (p = 0.001 and p = 0.042, respectively). The groups did not differ for the change in serum NTx, a specific systemic marker of osteoclastic bone resorption. However, the change in serum NTx correlated significantly with the increase in erosion score in the total study population and in the control group (r = 0.41, p = 0.01 and r = 0.48, p = 0.034, respectively). CONCLUSION: Etidronate therapy did not prevent radiologic progression in patients with RA, but the decline in serum PINP and ICTP concentrations suggests a favorable effect on general bone metabolism. Correlation between the change in serum NTx and worsening of the erosion score provides biochemical evidence that osteoclast is the principal cell type responsible for focal bone resorption in RA.

Adult↗

PubMed2002

Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1.

Polymerization of the ECM proteins fibronectin and laminin has been shown to take place in close vicinity to the cell surface and be facilitated by beta(1) integrins (Lohikangas, L., Gullberg, D., and Johansson, S. (2001) Exp. Cell Res. 265, 135-144 and Wennerberg, K., Lohikangas, L., Gullberg, D., Pfaff, M., Johansson, S., and Fassler, R. (1996) J. Cell Biol. 132, 227-238). We have studied the role of collagen receptors, integrins alpha(11)beta(1) and alpha(2)beta(1), and fibronectin in collagen polymerization using fibronectin-deficient mouse embryonic fibroblast cell lines. In contrast to the earlier belief that collagen polymerization occurs via self-assembly of collagen molecules we show that a preformed fibronectin matrix is essential for collagen network formation and that collagen-binding integrins strongly enhance this process. Thus, collagen deposition is regulated by the cells, both indirectly through integrin alpha(5)beta(1)-dependent polymerization of fibronectin and directly through collagen-binding integrins.

Animals↗

PubMed2002

Increased expression of collagen types I and III in human skin as a consequence of radiotherapy.

To study the mechanisms of irradiation-induced fibrosis, the expression of types I and III collagen was analysed in radiotherapy-treated human skin. The subjects were ten randomly chosen women who had been treated for breast cancer with surgery and radiotherapy. The subjects ranged in age from 42 to 68 years (mean 53 years) and the time from treatment ranged from 7 to 94 months. The irradiated skin was compared with a corresponding healthy skin area in the same subject. Suction blisters were induced on both skin areas. The aminoterminal propeptides of types I and III collagen (PINP and PIIINP), which reflect actual in vivo skin collagen synthesis, were determined in the suction blister fluid using radioimmunoassays. mRNA of types I and III collagen were determined in skin specimens using a nonradioactive in situ hybridization (ISH) technique. Immunohistochemical staining for PINP was also performed. The level of PINP in suction blister fluid was increased more than threefold and the level of PIIINP more than twofold in irradiated skin compared to control skin. The number of cells containing type I and type III collagen mRNA was increased in the upper dermis of irradiated skin. Immunohistochemical staining showed the amount of PINP-positive fibroblasts to be increased in irradiated skin. We conclude that skin collagen gene expression is increased as a result of irradiation and this leads to fibrosis and thickening of the dermis.

Adult↗

PubMed2002

Mannose receptor-mediated regulation of serum glycoprotein homeostasis.

Carbohydrates are thought to function as tags that mark circulatory glycoproteins for rapid clearance. To examine the role of the mannose receptor (MR) in glycoprotein clearance, we generated mice genetically deficient in MR. MR-/- mice were defective in clearing proteins bearing accessible mannose and N-acetylglucosamine residues and had elevated levels of eight different lysosomal hydrolases. Proteomic analysis of MR-/- and control mouse sera showed that an additional 4 out of 52 proteins identified were elevated in MR-/- serum. Each of these is up-regulated during inflammation and wound healing. Thus, MR appears to operate as an essential regulator of serum glycoprotein homeostasis.

Animals↗

PubMed2002

Increased content of type III collagen at the rupture site of human Achilles tendon.

We compared the type I and III collagen amounts and cross-linked telopeptides at the rupture site and two other sites of the same tendon. Tendon samples of ten individuals with total Achilles tendon rupture and six healthy cadavers were collected. The newly synthesized type I and III procollagens were assessed by extracting the soluble propeptides PINP, PICP and PIIINP. The insoluble matrix was solubilized by heat denaturation and trypsin digestion. Hydroxyproline, the cross-linked telopeptide structures of type I (ICTP and SP 4) and III collagens (IIINTP) and the degradation product of type III collagen (tryptic PIIINP) were measured from the digests. The type III collagen content was significantly increased at the rupture site when compared to control sites (5- and 12-fold increased) or cadavers (5-fold increased). No changes in the amounts of newly synthesized type I and III procollagens were observed. The ICTP content decreased and the SP 4/ICTP ratio increased along with ageing, suggesting a structural change in the type of cross-link in the carboxyterminal telopeptide of type I collagen. Type III collagen has accumulated at the rupture site probably due to microtraumas and the subsequent healing process. The increased content of type III collagen can cause thinner collagen fibers, decrease the tensile strength and may finally result in total rupture of the tendon. The age-related change in the nature of the cross-link in the carboxyterminal telopeptide may contribute to this weakening.

Achilles Tendon↗

PubMedDate not supplied

Collagen formation in extracellular matrix of transplants of human transformed keratinocyte cell lines.

BACKGROUND, MATERIALS AND METHODS: The role of epithelial cell growth and neoplastic transformation on collagen formation and deposition in the extracellular matrix (ECM) was analyzed by culturing immortalized human epidermal cell lines and Ras-transformed benign and malignant clones on collagen gels as transplants. The lesions were analyzed for extent of growth and morphology of epithelial and mesenchymal components as well as synthesis and deposition of different collagens. RESULTS: Immortalized cell lines required up to 5 weeks of growth for a well-organized mesenchyme to develop; transplants of Ras-transformed benign clones needed 3 weeks and transplants of highly malignant clones only 2 weeks to form an organized stroma. In transplants of immortalized cells after 2 weeks of growth newly-synthesized collagen type I and type III were deposited in the mesenchyme adjacent to the muscle, forming a mature ECM, while ECM was absent adjacent to growing, differentiated, immortalized cells. In transplants of Ras-transformed benign clones the subepithelial ECM was immature at day 14, but it was forming fibers at the same time in transplants of malignant clones. These were seen as thin irregular fibers in immunohistochemistry, ultimately organized into fibrillar structures in similar locations to active synthesis detected by in situ hybridization. Depositions of crosslinked mature type I collagen occurred later in similar locations. Type III collagen synthesis and deposition was most prominent in transplants of malignant cell clones, with degradation and destruction of the extracellular matrix around invading islets of malignant cells. CONCLUSION: The development of mesenchyme was directly related to duration of growth of transplants and degree of malignancy; mesenchyme organization was inversely related to differentiation of the epithelial cells. The results showed the usefulness of the transplant model in studies on cell and tissue growth and organization.

Cell Cycle↗

PubMedDate not supplied

Elevated preoperative serum ICTP is a prognostic factor for overall and disease-free survival in breast cancer.

The aim of this study was to evaluate the prognostic value of preoperative concentrations of the serum markers of type I collagen synthesis (PINP, PICP) and degradation (ICTP) in breast cancer. One hundred and eighty-four breast cancer patients without advanced disease were enrolled. Preoperative serum markers of type I collagen were assessed with specific radioimmunoassays. Elevated preoperative serum concentrations of ICTP (>4.9 microg/l) correlated statistically significantly with a poor prognosis for the breast cancer (P=0.0004) and shorter disease-free survival (P=0.02), and multivariate regression analysis likewise showed an elevated ICTP concentration (P=0.008), high grade (P=0.03) and high pathological stage (P=0.02) to be risk factors for poor survival. Sixty-five out of the 184 patients developed metastatic disease during the follow-up. The median follow-up time was 62 months (range 6-111 months). High ICTP (P=0.02) and large numbers of metastatic nodules (P=0.002) were prognostic factors for shorter disease-free survival in multivariate regression analysis. PINP and PICP had no significant prognostic value with respect to either overall or disease-free survival in this analysis. Our results indicate that preoperatively elevated serum ICTP is a prognostic factor in breast cancer, the measurement of which should improve the accuracy of predictions of the clinical outcome.

Adult↗

PubMedDate not supplied

Comparison of carboxyterminal telopeptide of type I collagen (ICTP) and CA 125 as predictors of prognosis in ovarian cancer.

BACKGROUND: The clinical significance of the carboxyterminal telopeptide of type I (ICTP) as a predictor of prognosis is insufficiently known in ovarian cancer. Therefore, we compared the prognostic accuracy of ICTP and CA 125 and their combination with each other and with the aminoterminal propeptide of type III procollagen (PIIINP) and clinical prognosticators. PATIENTS AND METHODS: Fifty-five epithelial ovarian cancer patients treated in Oulu University Hospital, Finland, from 1989-1995, were enrolled in this study. Cytoreduction was performed as completely as possible. The preoperative serum concentrations of the biochemical markers were determined using commercial kits. RESULTS: In univariate analysis, each biochemical marker and all conventional prognostic indicators, with the exception of histological subtype, correlated significantly with survival. In multivariate Cox analysis on biochemical and clinical markers, ICTP alone and ICTP + CA 125, but not CA 125 alone, proved useful indicators of overall survival. The combination of ICTP and CA 125, however, added no essential information compared to that obtained with ICTP alone. CONCLUSION: The ICTP test seems to be a clinically useful predictor of the clinical behavior of ovarian cancer. An increased serum ICTP concentration may reflect the spreading and aggressiveness of invasively growing ovarian cancer.

Adult↗