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.     

Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum

The aminoterminal propeptide of type I procollagen (PINP) in serum is a sensitive indicator of the synthesis of type I collagen. Four assays are available for PINP, two of them (intact PINP assays) measure the intact propeptide and the other two (total PINP assays) also detect a smaller antigen in serum. In many clinical situations, these assays give similar information, but renal insufficiency increases the concentration of the smaller antigen, influencing both the apparent concentration of PINP and assay calibration. Serum PINP is mostly affected by changes in bone metabolism. In infants and children, the concentration is much higher than in adults. Serum PINP (s-PINP) is a useful indicator of disease activity in Paget's disease of bone, in bone metastases of osteoblastic nature, and in the follow-up of treatment of osteoporosis. The IFCC and IOF recently recommended the use of s-PINP as a reference marker for bone formation in studies concerning fracture risk assessment and treatment response.     

Type I and type III collagen synthesis and composition in the valve matrix in aortic valve stenosis

Changes in the collagenous matrix may contribute to the pathogenesis and progression of human aortic valve stenosis (AS). To evaluate the significance of collagen I and III in the pathogenesis of AS, we studied their synthesis in diseased valves. Type I and type III collagen mRNA expression and the immunohistochemical localization of the collagen antigens were studied from 36 AS and 2 normal aortic valves. The concentrations of propeptides and telopeptide structure of type I (PINP, PICP, and ICTP) and those of III collagens (PIIINP and IIINTP) were measured by radioimmunoassays in soluble tissue extracts and trypsin-solubilized calcified and non-calcified matrices of 11 AS and 24 healthy aortic valves of different ages. The synthesis of type I collagen, localized in the myofibroblasts adjacent to calcified nodules, was two- to three-fold in the AS samples compared to the controls. The proportion of collagen in the total protein fraction was 90% in the healthy valves, 50% in the non-calcified matrix, and 10% in the calcified matrix of AS valves. In the calcified valves, the ICTP content was six-fold compared to the age-matched controls and two-fold compared to the young control group. In the controls, the amount of ICTP in type I collagen decreased with age (r=-0.908, p<0.001) and was replaced by other cross-linked C-telopeptide structure. The concentration of type III collagen decreased during aging (r=-0.753, p<0.001). The decrease in total collagen content, despite the increase in type I collagen synthesis indicates an increase in collagen turnover in AS. The calcification of the aortic valves is accompanied by increased amount of ICTP in type I collagen.     

Gelsolin amyloid angiopathy causes severe disruption of the arterial wall

Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi‐quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA.     

Type I and type III collagen metabolites in adult osteosarcoma patients.

Three biochemical markers of collagen metabolism were measured in 39 osteosarcoma patients. The pretreatment values did not predict outcome, and the markers showed no consistent change upon development of metastases. Both the age of the patients and the multimodality therapy affected the collagen metabolites. These findings emphasise the need for cautious interpretation of tumour-associated markers.     

Assessment of bone formation by biochemical markers in metabolic bone disease: Separation between osteoblastic activity at the cell and tissue level

Summary In this study, serum levels of classical serum markers of bone formation [carboxyterminal propeptide of procollagen type I (S-PICP), bone Gla protein (S-BGP)], and total alkaline phosphatase (S-AP)) were related to the calcium kinetic index of whole skeletal mineralization rate (m) by regression analysis in a variety of metabolic bone diseases. For each disease, the regression coefficient (r) as well as the fraction: standard error of estimate/mean dependent variable (SEE/Y) were determined. In a group of 19 normals, only the regression of S-PICP on m reached significance (r=0,53, P<0.02, SEE/Y=0.44), whereas regressions of S-AP and S-BGP on m were nonsignificant. In a pooled material of high-and low-turnover bone diseases without mineralization defects or spinal fracture [myxedema, thyrotoxicosis, and primary hyperparathyroidism (n=48)], a highly significant positive regression of S-PICP on m was demonstrable (r=0.50, SEE/Y=0.63, P<0.001). The regression coefficients obtained for S-BGP and S-AP were 0.74 (P<0.001, SEE/Y=0.41) and 0.42 (P<0.01, SEE/Y=0.55), respectively. When analyzing individual diseases in this group, significant differences among the three markers were detectable. In a group of 52 osteoporotics, S-PICP correlated significantly to m (r=0.49, P<0.001, SEE/Y=0.50). Corresponding r-values for S-BGP and S-AP were 0.21 (NS) and 0.48 (P<0.001, SEE/Y=0.61), respectively.Patients with histologically proven osteomalacia revealed no correlation between S-PICP and m. S-BGP and S-AP were, however. significantly correlated to m [r=0.92 (SEE/Y=0.46) and r=0.82 (SEE/Y=0.57), respectively], indicating that S-BGP and S-AP reflect mineralization activity, whereas S-PICP reflects matrix formation only. In order to study cellular production of the three formative markers, organ level production rate was normalized for bone turnover by division with m. For each marker, the fraction (bone marker concentration/m) was calculated and the means compared with normal controls. S-PICP/m was found to be lower than normal in primary hyperparathyroidism (P<0.01) and thyrotoxicosis (P<0.001). S-AP/m was elevated in myxedema (P<0.05), osteoporosis (P<0.001), and osteomalacia (P<0.01). S-BGP/m only deviated significantly from normal in osteomalacia (P<0.001).In conclusion, we found S-BGP to be a reliable marker of organ level mineralization rate in all diseases studied, whereas the regressions of S-AP and S-PICP revealed disease-specific discrepancies. This study also revealed significant alterations in the osteoblastic production rate of the three formative markers at the level of individual osteoblasts that have to be taken into account when comparing bone marker concentrations with other indices reflecting bone formation (e.g., calcium kinetics and histomorphometry).     

Serum osteocalcin and carboxyterminal propeptide of type I procollagen in rheumatoid arthritis.

OBJECTIVES--Previous reports indicate that serum osteocalcin (serum bone GLA protein (S-BGP)) and carboxyterminal propeptide of type I procollagen (PICP) can be used as indicators of bone formation and turnover. The purpose of this study was to assess the activity of bone formation in patients with rheumatoid arthritis (RA) using S-BGP and S-PICP. The biochemical data were compared with data obtained from bone histomorphometry. METHODS--Concentrations of S-BGP and S-PICP were measured in 119 women with RA aged 30-66 years and 47 healthy female controls matched for age. Bone histomorphometry of iliac crest samples was performed in 107 patients with RA. RESULTS--Weak to moderate correlations between the serum markers and histological bone formation parameters were found. Concentrations of S-BGP and S-PICP were significantly decreased in patients with RA compared with the controls (S-BGP 7.2 (2.3) v 8.7 (2.1) micrograms/l; S-PICP 105 (32) v 117 (38) micrograms/l. The lowest values were found in patients with recent onset RA. CONCLUSIONS--These findings suggest that bone formation and bone remodelling are generally reduced in patients with RA.     

Accumulation of laminin and type IV collagen in the kidney in congenital nephrosis

The aim of this study was to evaluate qualitatively the occurrence of the basement membrane proteins laminin and type IV collagen in the kidneys of ten infants with congenital nephrotic syndrome of the Finnish type (CNF) aged from 3 to 23 months and to compare the results with those for age-matched controls. A slow accumulation of basement membrane (BM) material occurred in the glomerular mesangium, the peripheral capillaries, around atrophied tubules, and the renal vessels in the course of the disease. The staining pattern of accumulated material depended on the duration of the disease and subsequent renal parenchymal damage. Young CNF patients with slight morphological changes in the kidney had only focal and minimal increases in the amounts of mesangial matrix, but as the disease advanced, so the BMs of the glomerular capillaries, renal arteries, and atrophied tubules also became involved and were thicker than normal. The staining reaction was in all patients similar with antibodies against the fragment P1 of laminin and the 7-S domain of type IV collagen. The accumulation of BM material in CNF kidneys is regarded as a secondary phenomenon induced by an unknown pathogenetic defect in the metabolism of some BM component.     

Simultaneous evaluation of epithelial cell function by CA 125 and stromal cell activity by aminoterminal propeptide of type III procollagen (PIIINP) in ovarian carcinoma

Serum concentrations of CA 125 and the aminoterminal propeptide of type III procollagen (PIIINP) were measured in 50 patients with clinical stage I or II (N = 16) and stage III or IV (N = 34) ovarian carcinoma before and during cytotoxic chemotherapy. Initially pathological concentrations of CA 125 were found in 92% of all patients and 100% of those in clinical stages II, III and IV. The concentration of PIIINP was at pathological levels in 71% of patients. Serum concentrations of CA 125 (P = 0.04) and PIIINP (P = 0.005) were higher in stages III and IV than in stages I and II. Initial concentration of PIIINP, but not of CA 125, was significantly (P less than or equal to 0.001) higher in the 19 patients who died of the malignancy than in the 31 patients alive at the end of the follow-up period. There was a significant inverse correlation (P = 0.01) between the initial PIIINP values and the survival time among patients with a poor prognosis. Initial concentration of CA 125 was of no prognostic value. During the follow-up, the serum concentrations of CA 125 and PIIINP correlated closely with clinical changes in the disease. Either or both of the tumour markers increased or remained at pathological levels before clinical relapse in patients who had initially responded. PIIINP was a more accurate marker (84%) than CA 125 (63%) in this respect. The information obtained from CA 125 and PIIINP concentrations was identical in 65% and complementary in 33% of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the menopause and hormone replacement therapy on the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen

We investigated the effect of the menopause and postmenopausal hormone replacement therapy (HRT) on the serum concentration of carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP), a potential new biochemical marker of bone resorption. A group of 44 healthy postmenopausal women, aged 45–54 years, had about 19% higher serum ICTP than did a group of 42 healthy premenopausal women aged 35–50 years (3.6±0.8 µg/l v 3.0±0.7 µg/l (mean ±SD);p<0.01), although there was a large overlap in the values. The 44 postmenopausal women also participated in a longitudinal clinical study, in which 20 received HRT and 24 received a placebo. Compared with the placebo group, those who received HRT had a significant (p<0.05) decrease in ICTP of about 12% at the end of 1 year of treatment, but again there was considerable overlap in the values. The menopause-and HRT-induced changes in ICTP were less than those seen in serum osteocalcin, serum total alkaline phosphatase, and fasting urinary excretion of hydroxyproline, calcium, pyridinoline and deoxypyridinoline. We conclude that the menopause increases and HRT decreases ICTP, although these changes are less pronounced than those seen in other biochemical markers of bone turnover.