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PubMed1987

Modulation of fibronectin gene expression in human mononuclear phagocytes.

Under some conditions, mononuclear phagocytes spontaneously synthesize and release fibronectin, an extracellular matrix glycoprotein with versatile effects on cell-matrix interactions. To gain insight into the processes that modulate the level of fibronectin secretion by these cells, we used monocytes, in vitro matured monocytes and alveolar macrophages as models to compare fibronectin mRNA levels and fibronectin secretion in a variety of circumstances. Using Northern analysis and dot-blot analysis with a 32P-labeled human fibronectin cDNA probe, we evaluated steady-state mRNA levels and a human fibronectin-specific ELISA was used to evaluate fibronectin secretion. In all cases the amounts of fibronectin secreted paralleled fibronectin mRNA levels. Specifically (a) when fibronectin mRNA was undetectable, as in the case of normal blood monocytes, no fibronectin was secreted, but whenever fibronectin mRNA was present, as in normal alveolar macrophages, fibronectin was secreted by the cells; (b) as monocytes matured into macrophages in vitro, the cells began to express fibronectin mRNA and the cells secreted fibronectin; (c) when alveolar macrophages were activated with surface stimuli such as lipopolysaccharide (LPS) or immune complexes, fibronectin mRNA levels decreased and in parallel, the cells secreted less fibronectin; (d) in idiopathic pulmonary fibrosis (IPF), alveolar macrophages contained severalfold more fibronectin mRNA transcripts that normal and the cells spontaneously secreted severalfold more fibronectin than normal; and (e) when IPF alveolar macrophages were placed in culture the fibronectin mRNA levels in the cells decreased with time, and concurrently the amounts of fibronectin produced per unit time continually decreased. The observation of a strict concordance of fibronectin mRNA levels and fibronectin release by mononuclear phagocytes suggests that, at least in many circumstances, fibronectin secretion by mononuclear phagocytes is controlled by steady-state levels of fibronectin mRNA.

Adult↗
PubMed1989

Molecular and immunologic differences in canine fibronectins from articular cartilage and plasma.

Two new monoclonal antibodies (Mabs) which reacted with canine fibronectin were produced and characterized. Data supported the conclusion that the epitope recognized by Mab 1H9A4 is within the first three Type III homology repeats of the Hep 2 domain and that the epitope for Mab 13G3B7 is within the last Type III homology repeat of fibronectin. These antibodies, along with three others, Mabs IST-2, IST-7, and IST-9, produced and characterized in the laboratories of L. Zardi of Genoa, Italy, were used to characterize canine cartilage and plasma fibronectin. In addition, cartilage explants were labeled with [35S]methionine in order to characterize newly synthesized cartilage fibronectin. The following observations were made. (i) Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (NaDodSO4-PAGE) of reduced canine plasma fibronectin revealed a characteristic doublet; reduced cartilage fibronectin revealed two major bands and one minor band. The lower molecular weight band was 10 kDa less than the beta subunit of plasma fibronectin. In Western blots, this band stained with Mab 1H9A4 but failed to react with Mab 13G3B7. (ii) Western blots of thermolysin and trypsin digests of cartilage fibronectin revealed cleavage patterns which differed from those obtained from digestions of plasma fibronectin. (iii) The ED-A sequence, detected by Mab IST-9, was present in less than 2% of the cartilage fibronectins. (iv) NaDodSO4-PAGE of purified and reduced 35S-labeled fibronectin revealed two major radioactive bands and one minor radioactive band which comigrated with the fibronectin from the cartilage but not with plasma fibronectin. We concluded that like "cellular" fibronectin, the ratio of alpha-type subunits to beta subunits was greater than 4 to 1 in cartilage fibronectin compared to 1.25 to 1 for plasma fibronectin; however, cartilage fibronectin was not a cellular fibronectin by the criterion of the presence of the ED-A sequence. Another difference between plasma and cartilage fibronectin was the presence in cartilage fibronectin of a subpopulation of subunits on which the last Type III homology repeat could not be detected. Biosynthetic data were consistent with the concept that cartilage fibronectin originates from local synthesis by the chondrocyte.

Animals↗
PubMed2005

Fetal fibronectin as a predictor of vaginal birth in nulliparas undergoing preinduction cervical ripening.

OBJECTIVE: We sought to evaluate whether the presence of a positive fetal fibronectin (> or = 50 ng/mL) in nulliparous women undergoing preinduction cervical ripening with the intracervical Foley catheter predicted vaginal birth. METHODS: This was a prospective blinded observational trial of nulliparous women undergoing preinduction cervical ripening. We excluded women who had a contraindication to vaginal birth. Cervical and vaginal fetal fibronectin specimens were obtained before preinduction cervical ripening with an intracervical Foley catheter. The managing obstetrician was blinded to these results. RESULTS: A total of 241 women met the inclusion criteria, of which 54.4% delivered vaginally. There was no difference in the rate of vaginal delivery among women with either a positive cervical fetal fibronectin (positive fetal fibronectin 55.8% compared with negative fetal fibronectin 53.3%, P = .70) or positive vaginal fetal fibronectin (positive fetal fibronectin 57.6% compared with negative fetal fibronectin 53.3%, P = .56). Women with a positive cervical fetal fibronectin did have a shorter duration of cervical ripening (fetal fibronectin-positive 229 +/- 220 minutes compared with fetal fibronectin-negative 379 +/- 193 minutes, P < .05), duration of oxytocin (fetal fibronectin-positive 655 +/- 555 minutes compared with fetal fibronectin-negative 731.5 +/- 342 minutes, P < .025) and required lower maximal doses of oxytocin (fetal fibronectin-positive 18.4 mIU/min compared with fetal fibronectin-negative 21.8 mIU/min, P = .005). Women with a positive vaginal fetal fibronectin demonstrated only a shorter duration of cervical ripening compared with their fetal fibronectin negative counterparts (fetal fibronectin-positive 300 +/- 216 minutes compared with fetal fibronectin-negative 345 +/- 201 minutes, P < .05). CONCLUSION: Fetal fibronectin does not predict vaginal delivery in nulliparous women requiring preinduction cervical ripening. LEVEL OF EVIDENCE: II-2.

Adult↗
PubMed2000

Fibronectin as a potent inhibitor of calcium oxalate urolithiasis.

PURPOSE: Fibronectin (230 kD.) is a multifunctional alpha2-glycoprotein distributed throughout the extracellular matrix and body fluids. Many investigators have demonstrated that fibronectin, because of its cell adhesive action, is related to biological processes such as morphogenesis, wound healing and metastasis. Recent studies have shown that a variety of molecules, including fibronectin, inhibit endocytosis of calcium oxalate crystals in vitro. We investigated other roles of fibronectin in calcium oxalate stone formation. MATERIALS AND METHODS: Immunoblotting of the crystal surface binding substance obtained from pooled healthy male urine samples was used to analyze whether fibronectin was adsorbed onto the surface of calcium oxalate crystals. To clarify the relationship between fibronectin and calcium oxalate crystals, we performed 6 experiments. Experiment 1 was immunohistochemical examination of fibronectin expression in stone forming rat model kidneys, and experiment 2 examined the fibronectin content of stone forming rat kidney models with the enzyme-linked immunosorbent assay. Experiment 3 was designed to determine fibronectin content of Madin-Darby canine kidney (MDCK) cells stimulated by addition of calcium oxalate crystals and experiment 4 identified the inhibitory effect of fibronectin on calcium oxalate crystal growth by the seed crystal method. For experiment 5 we used an aggregometer system to clarify the inhibitory effect of fibronectin on calcium oxalate crystal aggregation and experiment 6 examined the inhibitory effect of fibronectin on the adhesion of calcium oxalate crystals to MDCK cells. RESULTS: In the crystal surface binding substance immunoreactive bands at 230 kD., which correspond to the molecular weight of fibronectin, were detected by Western blot analysis. In stone forming rat kidneys strong expression of fibronectin was found on the renal tubules to which the crystals were attached. The fibronectin content of these kidneys was significantly greater than that of kidneys without calcium oxalate crystals. The fibronectin content of MDCK cells tended to increase in proportion to the concentration of calcium oxalate crystals added to the culture medium. The growth inhibition assay showed that the inhibitory effect of fibronectin on calcium oxalate crystal growth was small in relation to the quantity of fibronectin excreted. However, fibronectin had inhibitory effects on calcium oxalate crystal aggregation and adhesion of the crystals to MDCK cells. CONCLUSIONS: Fibronectin secretion can be stimulated by calcium oxalate crystals, and this protein, which is excreted from the tubular cells, may inhibit calcium oxalate crystal aggregation and attachment to cells.

Animals↗
PubMed1990

Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules.

The capacity of purified fibronectin to costimulate human T cell DNA synthesis was examined. Low concentrations of immobilized fibronectin, but not soluble fibronectin, augmented anti-CD3-induced proliferation of highly purified human T cells. In the absence of anti-CD3 stimulation, immobilized fibronectin did not induce T cell proliferation alone or in the presence of IL-2 or phorbol dibutyrate. Although fibronectin is present in high concentrations in the serum, immobilized fibronectin was able to costimulate T cell proliferation when cells were cultured in serum-containing medium. Immobilized collagen type I did not enhance anti-CD3 stimulated T cell responses, whereas gelatin (denatured collagen) and laminin were able to enhance anti-CD3 stimulated T cell responses modestly. The effects of gelatin, however, appeared to be indirect, because it could not enhance responses in medium devoid of fibronectin. Immobilized fibronectin enhanced anti-CD3 induced proliferation of both CD45RA dim and CD45RA bright subsets within both the CD4+ and CD8+ subpopulations of T cells, although cells with the CD45RA dim phenotype were costimulated by lower concentrations of immobilized fibronectin. Enhancement of anti-CD3 induced proliferation by immobilized fibronectin was completely inhibited by a mAb to CD29, the integrin beta 1-chain (4B4) and not by a variety of other mAb. In contrast to its effects on proliferation, 4B4 only partially blocked T cell binding to anti-CD3 and fibronectin-coated macrowells. These findings suggested that the interaction between fibronectin and its receptor transduced a signal to the T cell and did not merely stabilize the interaction between anti-CD3 and the CD3 complex. Further experiments confirmed this observation. Thus fibronectin could enhance anti-CD3 responses when it was immobilized to a separate surface. The augmentation of anti-CD3 stimulated proliferation induced by immobilized fibronectin was also inhibited partially by mAb to either VLA-4 or VLA-5 and completely by a combination of the two mAb. The mAb to VLA-4 not only blocked the capacity of immobilized fibronectin to enhance anti-CD3-induced T cell proliferation but also directly costimulated T cell responses. Thus, at least two fibronectin receptors are involved in fibronectin-mediated costimulation of T cell proliferation. These studies indicate that signals are transduced through the fibronectin receptors, VLA-4 and VLA-5, that augment T cell responses and therefore implicate the extracellular matrix protein fibronectin as an important influence regulating T cell responsiveness in vivo.

Antibodies, Monoclonal↗
PubMed1985

Role of factor VIII-von Willebrand factor and fibronectin in the interaction of platelets in flowing blood with monomeric and fibrillar human collagen types I and III.

Platelet adhesion to monomeric collagen types I and III, which were purified from human umbilical arteries, was studied in a perfusion chamber under well defined flow conditions. For this purpose, glass coverslips were coated with 20-30 micrograms/cm2 of collagen types I and III by spraying a solution of these collagens with a retouching air brush. Platelet deposition increased with the time of perfusion. Adhesion to both collagen types was similar in the first 3 min, but increased platelet deposition occurred on collagen type III after 3 min due to thrombus formation. Adhesion at a shear rate of 800 s-1 was strongly impaired with plasma of a patient with von Willebrand's disease or with fibronectin-free plasma. Addition of purified fibronectin to fibronectin-free plasma restored adhesion to the level obtained with normal plasma. Platelet deposition in normal plasma increased with increasing shear rates. Platelet deposition in VWD-plasma was normal at 490 s-1, but there was no increase at higher shear rates. Platelet deposition in fibronectin-free plasma was diminished at all shear rates studied from 490 to 1,300 s-1. Perfusion with a human albumin solution (HAS) to which purified Factor VIII-von Willebrand factor complex (FVIII-VWF) and fibronectin had been added gave similar platelet deposition as with normal plasma. Preincubation of collagen with FVIII-VWF and perfusion with HAS containing fibronectin, or, conversely, preincubation with fibronectin and perfusion with HAS containing FVIII-VWF, also resulted in adhesion similar to that observed in normal plasma. Similar adhesion was also observed after preincubation with both FVIII-VWF and fibronectin and subsequent perfusion with HAS alone. Sequential preincubations with first FVIII-VWF and then fibronectin, or with first fibronectin and then FVIII-VWF followed by perfusion with HAS, also gave a similar adhesion as observed with normal plasma. These data indicate that platelet adhesion to monomeric collagen types I and III is dependent on both FVIII-VWF and fibronectin. FVIII-VWF is only required at relatively high shear rates; fibronectin also at relatively low shear rates. Their complementary role in platelet adhesion suggests separate binding sites for FVIII-VWF and fibronectin on collagen. Platelet deposition on performed fibrils of collagen types I and III was also studied. Initial adhesion expressed as percentage surface coverage was similar to that found with monomeric collagen, but thrombus formation was much enhanced. Adhesion on fibrillar collagen at 800 s(-1) was impaired in VWD-plasma and fibronectin-free plasma, and was restored by addition of purified fibronectin to fibronectin-free plasma. When perfusions were performed with HAS, only addition of FVIII-VWF was required for optimal adhesion to fibrillar collagen; addition of fibronectin had no effect. These data are in contrast to the studies with monomeric collagens described above, in which the addition of both FVIII-VWF and fibronectin was required. These data are also in contrast to the observation that in plasma both FVIII-VWF and fibronectin are required for optimal adhesion to fibrillar collagen.

Blood Coagulation Factors↗
PubMed2000

Fibronectin polymerization stimulates cell growth by RGD-dependent and -independent mechanisms.

Many aspects of cell behavior are regulated by cell-extracellular matrix interactions, including cell migration and cell growth. We previously showed that the addition of soluble fibronectin to collagen-adherent fibronectin-null cells enhances cell growth. This growth-promoting effect of fibronectin depended upon the deposition of fibronectin into the extracellular matrix; occupancy and clustering of fibronectin-binding integrins was not sufficient to trigger enhanced cell growth. To determine whether the binding of integrins to fibronectin's RGD site is required for fibronectin-enhanced cell growth, the ability of fibronectin lacking the integrin-binding RGD site (FN(Delta)RGD) to promote cell growth was tested. FN(Delta)RGD promoted cell growth when used as an adhesive substrate or when added in solution to collagen-adherent fibronectin-null cells. Addition of FN(Delta)RGD to collagen-adherent fibronectin-null cells resulted in a 1.6-1.8x increase in cell growth in comparison with cells grown in the absence of fibronectin. The growth-promoting effects of FN(Delta)RGD and wild-type fibronectin were blocked by inhibitors of fibronectin polymerization, including the anti-fibronectin antibody, L8. In addition, FN(Delta)RGD-induced cell growth was completely inhibited by the addition of heparin, and was partially blocked by either heparitinase-treatment or by addition of recombinant fibronectin heparin-binding domain. Heparin and heparitinase-treatment also partially blocked the growth-promoting effects of wild-type fibronectin, as well as the deposition of wild-type fibronectin into the extracellular matrix. These data suggest that cell surface heparan-sulfate proteoglycans contribute to the growth-promoting effects of FN(Delta)RGD and wild-type fibronectin. Addition of heparin, treatment with heparitinase, or incubation with monoclonal antibody L8 all inhibited the formation of short linear FN(Delta)RGD fibrils on the cell surface. Inhibitory (beta)1 integrin antibodies had no effect on FN(Delta)RGD fibril formation, FN(Delta)RGD-induced cell growth, or cell adhesion on FN(Delta)RGD-coated substrates. These data suggest that fibronectin fibril formation can promote cell growth by a novel mechanism that is independent of RGD-integrin binding, and that involves cell surface proteoglycans.

Animals↗