Biomarkers of connective tissue aging: biosynthesis of fibronectin, collagen type III, and elastase.
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Aging↗
Biomedical subjects
J Labat-Robert
Publications and source records attributed to J Labat-Robert.
Cell-matrix interactions in the genesis of arteriosclerosis and atheroma. Effect of aging.
The progression of atheroarteriosclerosis was shown to be age dependent. This designation covers two separate entities: arteriosclerosis, the progressive and diffuse hardening of the walls of arteries with loss of elasticity, and atheromatous plaque formation, which can start early in life according to nutrition and genetic factors (LDL-receptor expression). Lipoprotein-receptor interactions play a crucial role in lipidic plaque formation. There is, however, no indication that the diffuse hardening of the vascular wall would also be influenced by these mechanisms. We described recently a high-affinity receptor for elastin peptides, present on smooth muscle cells, fibroblasts, and also on monocytes and PMNs. When activated, this receptor will increase intracellular calcium. Circulating elastin peptides were determined by a sensitive Elisa method and found to be between 0.1 and 20 micrograms/ml, in the range of activation of the elastin receptor. They increase in obliterative arteriopathies and type IIb hyperlipidemia. Elastolysis accompanies aging and vascular pathology; the sensitivity of this receptor changes with age, intracellular Ca++ increases, but the receptor appears to be uncoupled from its normal transmission mechanism. These results may well explain the increasing diffuse calcification of the vessel wall. The previously demonstrated potentiation of cholesterol deposition in elastic fibers by calcium is in agreement with simultaneous deposition of calcium and lipids. The recent demonstration of the efficient competition of fibronectin for LDL in proteoglycan-LDL complexes suggests that this reaction may be involved in foam cell formation by the opsonization of LDL for phagocytosis. Fibronectin was shown to accumulate in atherosclerotic plaques. Altogether these recent results confirm the importance of cell-matrix interactions in atherogenesis and lead to a better understanding of the age dependence of these disease processes.
Aging↗
UVA- and UVB-induced changes in collagen and fibronectin biosynthesis in the skin of hairless mice.
The modifications induced in hairless mouse skin by chronic UV irradiation were investigated. Skin explant cultures were used to study UVA- and UVB-induced changes occurring in interstitial collagen (type I and type III) and fibronectin biosynthesis. To study the long-term effects, albino hairless mice were irradiated with UVA radiation alone from two sources with different spectral qualities or with UVB. UVA and UVB radiation produced a significant increase in the ratio of type III to type I collagen (more than 100% for UVA-irradiated skin and about 60% for UVB-irradiated skin) accompanied by a significantly increased fibronectin biosynthesis (50% or more in all irradiated groups). Irradiation with either UVA or UVB alone had no significant effect on the total collagen synthesis and resulted in only a slight decrease in the total collagen content of the skin determined as hydroxyproline. This decrease was significant only in the case of the group irradiated with UVA (xenon) (decrease of 25%, expressed as micrograms of hydroxyproline per milligram wet weight). A significant decrease in collagen hydroxylation (expressed as radioactive hydroxyproline/radioactive hydroxyproline plus proline in neosynthesized collagen) was observed of about 50% in skin irradiated with UVA (xenon) but not in UVB-treated skin. Several of the above modifications (increased fibronectin biosynthesis, increased collagen type III to type I ratio) correspond to the modifications observed during the aging of non-irradiated hairless mice. Therefore it appears that UV irradiation accelerates the modifications of extracellular matrix biosynthesis observed during aging.
Amino Acids↗
In vivo evaluation of photoprotection against chronic ultraviolet-A irradiation by a new sunscreen Mexoryl SX.
In a previous study on the hairless mouse it was shown that sub-erythemal doses of pure UV-A enhanced the numerous changes normally observed during chronological aging. A new sunscreen (a bis-benzylidene campho sulfonic acid derivative) has been synthesized in our research laboratory (lambda max: 345 nm, epsilon: 47,000). Its photoprotective properties against UV-A induced damages were assessed in our mouse model. Three month old albino hairless mice were exposed for 1 y to suberythemal doses (35 J/cm2) of UV-A obtained from a xenon source filtered through a WG 345 filter. One group of animals was exposed untreated, the other received a formulation containing 5% of the sunscreen prior to irradiation. At the end of the study the cutaneous properties of protected mice were compared to those of unprotected animals and to 3 and 15 month old unirradiated controls. We found that the visible changes induced by UV-A irradiation were mainly sagging and wrinkling. Histological and electron microscopic alterations consisted of hyperkeratosis, increased density of elastic fibers with alteration of fiber orientation and increased glycosaminoglycan deposits. Biochemical changes consisted of decreases in total collagen and collagen hydroxylation and increases in both collagen III/I + III ratio and fibronectin biosynthesis. All these changes were reduced or abolished by the sunscreen.
Animals↗
[Integrins].
Cells and extracellular matrix components have complex interactions which are involved in many biological processes throughout the life span. These cell-matrix interactions are mediated by receptors, of which some are integral membrane proteins. The aim of this short article is to review the integrin family, the overall structure of integrins, their distribution and their role. These new data will undoubtedly contribute to improved understanding of the physiological and pathological processes involving connective tissues.
Extracellular Matrix↗
The in vivo systemic effect of human recombinant interleukin-1 beta on fibronectin in rats.
The in vivo systemic effect of interleukin (IL)-1 beta on plasma and cartilage fibronectin was studied in arthritic rats, as well as alpha 1-acid glycoprotein and albumin. Plasma fibronectin showed a 27% increase in the arthritic group, while alpha 1-acid glycoprotein increased 22-fold and albumin decreased by 46%. IL-1 effect depended on the administered dose. 2 micrograms injection significantly increased plasma fibronectin and alpha 1-acid glycoprotein. In cartilage, fibronectin was significantly modified in arthritic animals but increased in a dose-related manner after IL-1 treatment. As IL-1 increases fibronectin-degrading enzyme production and as some of these fragments can develop properties that do not possess the intact molecule, one can postulate a vicious circle in matrix degradation in the inflammatory process of the joint.
Animals↗
[Fragmentation of fibronectin in cystic fibrosis].
Fibronectin (FN) plays an important role in mediating cell-matrix interactions and also as an opsonin in the phagocytosis of some microorganisms. Due to its domain structure FN is easily attacked by proteolytic enzymes and especially by elastases. Some of the fragments possess original properties as potentiation of viral transformation or proteolytic activity absent in the intact molecule. Cystic fibrosis is frequently accompanied by infection with protease generating microorganisms, such as Pseudomonas aeruginosa. Polyacrylamide gel electrophoresis and immunoblotting revealed the presence of FN fragments in the plasma of patients with molecular weight between 30 and 100 kD. Purified plasma FN was rapidly hydrolyzed in fragments by the sputum of patients as well as by purified Pseudomonas elastase. The comparison of fragments detected in patients' plasma with those produced by in vitro proteolysis confirms the probability of in vivo fragmentation of FN in cystic fibrosis and suggests that several proteolytic enzymes, endogenous and of bacterial origin, might be involved.
Cystic Fibrosis↗
Biosynthesis and distribution of fibronectin in normal and osteoarthritic human cartilage.
The biosynthesis of fibronectin was determined in explants from normal and osteoarthritic human cartilage after metabolic labeling and immunoprecipitation. Each sample of osteoarthritic cartilage was divided into three regions taken at different distances from the eburnated bone area. Only full depth cartilage samples were taken into consideration. We could detect a low level of fibronectin biosynthesis in normal cartilage. In osteoarthritic cartilage increased synthesis of fibronectin was demonstrated, the most important in the region close to the eburnated area. Increased synthesis, although to a lower extent, was also demonstrated in the two other regions at increasing distances from the eburnated areas. Immuno-histological examinations performed on tissue samples and similar studies on articular chondrocyte cell cultures confirmed the accumulation of newly synthesized fibronectin in pathological conditions.
Cartilage, Articular↗
[Fibronectin, aging and related pathologies].
It could be demonstrated that plasma and tissue fibronectin (FN) increase with age. Some age dependent diseases as diabetes, osteoarthritis and Werner syndrome produce also an increase of tissue fibronectin biosynthesis. Plasma fibronectin decreases in diabetes and in breast cancer. Alternative splicing of the FN gene appears also to vary with age and in some related pathologies. Nutritional status and UV light also influence FN biosynthesis. It appears therefore that the determination of plasma FN and its isoforms as well as the study of tissue FN may be of interest for the study of chronological aging and related pathologies.
Age Factors↗
[Gastric mucus glycoproteins : structure, functions and pathology (author's transl)].
O-glycosylated glycoproteins are the main constituents of gastric mucus. They are responsible for its viscosity and for its gel-forming properties. Recent advances accomplished over the last years on its physical and chemical characterization are briefly reviewed. Many issues remain still unsettled concerning the modification of its structure and composition in diseases as well as details of its biosynthesis and its pharmacology.
Animals↗
Quantitative evaluation of the in vitro biosynthesis of gastric mucus glycoproteins. Standardization of the methodology.
For the evaluation of a normal or pathological function of gastric mucosa, a reproducible method for the estimation of the biosynthesis of mucus glycoproteins appears to be necessary. Rat gastric mucosal scrapings incorporate in vitro several labeled compounds such as 14C-U-D-glucose, 35SO4, 14C-I-L-fucose and L-G-3H-proline in glycoproteins similar to those synthetized in vivo by native mucosa. The aim of our present work is to describe in detail the procedure we use and to show its reproducibility in 9 separate experiments. Secreted glycoproteins (fraction II) and intracellular glycoproteins (fraction III) obtained during a 4 hours in vitro incubation of rat gastric mucosal scrapings at 37 degrees C in standardized conditions were separately studied. The protein and hexose contents, total incorporated radioactivity and specific radioactivity (cpm/mg protein) were determined in these two fractions. The protein content of fraction II from 2 rat gastric mucosal scrapings incubated in 5 ml was 2 mg +/- 0.4 SEM and its hexose was 38.7 mg per 100 mg protein +/- 3.9. Fraction III contained 6.3 mg protein +/- 1.3 and 15.7 mg hexose per 100 mg protein +/- 3.5. About 27% of the total radioactivity incorporated (from 14C-glucose) was in fraction II (+/- 2.6 SEM) and 73% (+/- 2.6 SEM) in the cell bound fraction III. The distribution of total radioactivity was quite similar to that of total proteins : about 25% proteins were in fraction II and 75% in fraction III with a SEM of about 5 to 10% of the average value. If the biosynthetic activity is expressed as specific radioactivity, i.e. the ratio of incorporated radioactivity to mg proteins, the average for both fraction II and fraction III was about 10,000 cpm/mg protein and the standard error of the mean values are +/- 5.2% of the mean for in vitro secreted mucus glycoproteins (fraction II) and 9.1% in the case of intracellular glycoproteins (fraction III). These values can be considered as a satisfactory index of reproducibility of the method of mucosal scrapings if performed as described above.
Animals↗
The effect of drugs and secretagogues on the biosynthesis of gastric mucins.
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Animals↗
Comparative specificities of trehalases from various species.
1. Using derivatives or non-symmetrical analogs of alpha,alpha-trehalose, we studied the catalytic specificities of trehalases from various species: Pseudomonas fluorescens, Melolontha vulgaris, porcine and human kidneys. 2. alpha,Beta-trehalose, beta,beta-trehalose, 6,6'dideoxy alpha,alpha-trehalose, alpha-D-xylopyranosyl alpha-D-xylopyranoside were shown to be neither substrates nor inhibitors. 3. 6'deoxy alpha,alpha-trehalose, alpha-D-glucopyranosyl alpha-D-xylopyranoside, alpha-D-allopyranosyl alpha-D-glucopyranoside and alpha-D-galactosyl alpha-D-glucopyranoside, which all possess an intact alpha-D-glucopyranosyl residue, were split by all these trehalases. 4. alpha-D-glucopyranosyl alpha-D-mannopyranoside, alpha,alpha-trehalosamine are competitive inhibitors. 5. These results show the importance of the primary alcohol group at C-6, of the equatorial configuration of the OH groups at C-2, C-3 and C-4 and of the modification of the structure at C-2 of the substrate for the catalytic activity.
Animals↗
Modifications of the biosynthesis of type-I and type-III collagens and fibronectin during diabetes and atherosclerosis.
Results show that diabetes, which is a major risk factor for arterio-atherosclerosis, mimicks an accelerated aging, at least as far as the thickening of basement membranes and fibronectin and collagen biosynthesis are concerned. A similar sequence of events could be demonstrated in human atherosclerotic plaque formation. In conclusion, we could demonstrate a disregulation of extracellular matrix components biosynthesis (type-III collagen and fibronectin) in diabetes and atherosclerosis.
Aged↗