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PubMed2006

Effect of transforming growth factor-beta on decorin and beta1 integrin expression during muscle development in chickens.

Myoblast-extracellular matrix interactions play a pivotal role in skeletal muscle development. Transforming growth factor-beta (TGF-beta) is a key regulator of muscle cell proliferation and differentiation. The level of TGF-beta expressed will affect the concentration of the extracellular matrix proteoglycan decorin and the cell surface beta1 integrin subunit. The decorin proteoglycan is a regulator of cell growth as well as the organization of the extracellular matrix. The beta1 integrin plays a role in muscle cell attachment, migration, and the formation of multinucleated myotubes. In the current study, chicken myogenic satellite cells isolated from the pectoralis major muscle from the chicken genetic muscle weakness, low score normal (LSN), and normal pectoralis major muscle were used to investigate TGF-beta expression as it relates to decorin and beta1 integrin mRNA expression. The LSN muscle defect is characterized by altered myotube formation and sarcomere structure, and the satellite cells have reduced proliferation and differentiation. The mRNA expression was measured by real-time quantitative reverse transcription PCR. The LSN condition has elevated expression of TGF-beta2 and TGF-beta4 with increased expression of decorin and decreased beta1 integrin during myogenic satellite cell proliferation and differentiation. Normal satellite cell cultures were treated with the addition of exogenous TGF-beta during differentiation to determine if the altered expression of LSN decorin and beta1 integrin was associated with TGF-beta expression. The addition of exogenous TGF-beta decreased decorin expression during differentiation and reduced beta1 integrin expression at 24 and 48 h of differentiation. These results suggested that alteration of decorin expression in the LSN myogenic satellite cells may occur by a mechanism involving factors in addition to TGF-beta, but the addition of exogenous TGF-beta did affect both decorin and beta1 integrin expression. These data, therefore, suggested that TGF-beta might play a pivotal role in chicken skeletal muscle formation through modulation of the expression of both extracellular matrix molecules and cellular receptors important in the control of cell migration and growth regulation.

Animals↗

PubMed2002

TNFalpha-induced apoptosis and integrin switching in human extravillous trophoblast cell line.

Differentiation of extravillous trophoblast cells (EVT) to an invasive phenotype plays an essential role in establishing and maintaining feto-placental organization during human pregnancy. A switch in integrin expression occurs during this differentiation and is accompanied by changes in the extracellular matrix (ECM). Alteration of EVT behavior is also modulated by cytokines. To investigate the molecular interactions involved in the EVT differentiation, we examined the effects of cytokines and ECM on the human EVT cell line, TCL1 cells. We found that tumor necrosis factor alpha (TNFalpha) induced apoptosis in TCL1 cells but not in JEG3 cells derived from choriocarcinoma while the addition of interleukin-1beta, leukemia inhibitory factor, or transforming growth factor had no effect on TCL1 cells. This apoptosis was suppressed when TCL1 cells were seeded on fibronectin (Fn), collagen type I (C1), collagen type IV (C4), or laminin (Ln). Wortmannin, a specific PI3 kinase inhibitor, inhibited this suppression. Spreading assays and adhesion blocking assays indicated that TCL1 cells express integrin-alpha5 and -alpha6 and beta1 and beta4 subunits. Adhesion on Fn is mediated by alpha5beta1, and adhesion on C1, C4, or Ln is mediated by alpha6beta1 integrins. TNFalpha suppressed alpha6 integrin expression and enhanced alpha1 integrin expression in a dose-dependent manner. In addition, aggregation of beta1 subunits on C4 was detected after addition of TNFalpha. Taken together, these results suggest that TNFalpha and ECM, through activation of PI3 kinase mediated by beta1 integrin signaling, might collaboratively regulate differentiation of trophoblast cells through integrin signaling in establishing and maintaining successful pregnancy.

Apoptosis↗

PubMed1995

A porcine homolog of human integrin alpha 6 is a differentiation antigen of granulosa cells.

To search for new molecules relating to the mechanism(s) of follicular differentiation, we raised a new monoclonal antibody (mAb), POG-2, which reacted with the surface of porcine ovarian granulosa cells. An immunohistological study revealed that the antigen appeared initially on the primary follicles. The antigen expression increased during follicular development, reached the highest level in small follicles 1-2 mm in diameter, and then decreased in the preovulatory follicles. The antigen was not detected on luteal cells in the CL. SDS-PAGE profiles of POG-2 antigen purified from isolated porcine granulosa cells by immunoaffinity chromatography indicated that it consisted of two proteins (120 and 130 kDa) and that the antigenic epitope of POG-2 was on the 120-kDa protein. We next purified a large amount of POG-2 antigen from the homogenate of porcine ovaries by immunoaffinity chromatography. Analysis of the partial amino acid sequence of the 120-kDa protein showed that 16 amino acids from the amino terminus were very similar to those of both human and murine mature integrin alpha 6, with 88% homology. SDS-PAGE profiles revealed that the 120-kDa protein was bound to a 28-30-kDa protein by a disulfide bond; this was compatible with the reported characteristics of human integrin alpha 6. We then examined the immunoreactive distribution of integrin alpha 6 using anti-integrin alpha 6 mAb GoH3. The staining profiles obtained with GoH3 were very similar to those obtained with POG-2. These findings showed that the molecule detected by POG-2 was a porcine homolog of human integrin alpha 6 and that integrin alpha 6 was a differentiation antigen of porcine granulosa cells, suggesting an involvement of integrins in follicular differentiation.

Amino Acid Sequence↗

PubMed2002

Microfilament-dependent movement of the beta3 integrin subunit within focal contacts of endothelial cells.

To gain insight into the dynamic properties of focal contacts, we induced expression of green fluorescent protein-tagged beta3 integrin (GFP-beta3) and actinin-1 (GFP-actinin-1) in endothelial cells. Both tagged proteins localize with alpha(v)beta3 integrin in focal contacts distributed towards the periphery of transfected cells. Labeled focal contacts migrate at about 0.1 mm/min in stationary live endothelial cells. We compared beta3 integrin and actinin-1 dynamics in focal contacts by using fluorescence recovery after photobleaching. Recovery of signal in bleached focal contacts that have incorporated actinin-1 is rapid and occurs within less than 4 min. This recovery is energy-dependent. In contrast, recovery of bleached focal contacts that contain GFP-beta3 integrin takes longer than 30 min. Yet, when a narrow stripe of fluorescence is bleached across a beta3 integrin-labeled focal contact, recovery is complete within 16 min. The latter recovery is energy-dependent and is blocked not only by actin-filament disrupting drugs but also by a myosin light chain kinase inhibitor. Thus, integrins are not immobile when incorporated into focal contacts, as some have suggested. We propose that integrins are mobile within the confines of focal contacts and that this mobility is supported by an actin-associated molecular motor.

Actin Cytoskeleton↗

PubMed2002

Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone.

The reasons why tumor cells metastasize to bone remain obscure. There is some evidence to support the theory that integrins (acting as cell surface adhesion receptors) play a role in mediating metastasis in certain organs. Here, we report that overexpression of a functionally active integrin alpha(v)b3 in Chinese hamster ovary (CHO) tumor cells drastically increased the incidence, number, and area of bone metastases in nude mice compared with those observed in mock-transfected CHO cells (CHO dhfr+) or in CHO cells expressing a functionally inactive integrin alpha(v)b3 (CHO beta3Delta744). Moreover, a breast cancer cell line (B02) established from bone metastases caused by MDA-MB-231 cells constitutively overexpressed integrin alpha(v)b3, whereas the cell surface expression level of other integrins remained unchanged. In vivo, the extent of bone metastases in B02-bearing mice was significantly increased compared with that of MDA-MB-231-bearing mice. In vitro, B02 cells and CHO cells expressing a functionally active integrin alpha(v)b3 exhibited substantially increased invasion of and adhesion to mineralized bone, bone sialoprotein, and collagen compared with those found with MDA-MB-231, CHO dhfr+, and CHO beta3Delta744 cells, respectively. Overall, our findings suggest that integrin alpha(v)b3 expression in tumor cells accelerates the development of osteolytic lesions, presumably through increased invasion of and adhesion to bone.

Animals↗

PubMed2001

Synergistic interaction of integrin and angiotensin II in activation of extracellular signal-regulated kinase pathways in vascular smooth muscle cells.

Integrins, major adhesion receptors and angiotensin II activate extracellular signal-regulated kinase (ERK) pathways and result in a mitogenic response such as the proliferation of vascular smooth muscle cells (VSMCs). We investigated mechanisms of collaboration or synergism between integrins and angiotensin II involving ERK pathways in VSMCs. Integrin activation by cell adhesion to fibronectin increased the phosphorylation level of focal adhesion kinase (FAK) upstream of the ERK pathway. angiotensin II induced a high increase in the phosphorylation level of FAK with integrin activation, but not in suspended cells. Integrin activation increased phosphorylation levels of ERK kinase (MEK) and ERK phosphorylation as well. Angiotensin II-induced MEK and ERK phosphorylation were retained even in suspended cells. Furthermore, with integrin activation, angiotensin II induced a much larger increase in the phosphorylation levels of MEK and ERK. These results suggest that simultaneous stimulation of integrin and angiotensin II receptors cause synergistic interaction in the activation of ERK pathway, possibly via phosphorylation of FAK, which may play a critical role in angiotensin II-mediated mitogenic response in VSMCs.

Angiotensin II↗

PubMed1995

Cytokine-mediated modulation of integrin, ICAM-1 and CD44 expression on human uveal melanoma cells in vitro.

Adhesion molecules are likely to play a role in the process of tumour progression. We investigated the expression of integrins, ICAM-1, and CD44 and the influence of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), and tumour necrosis factor-alpha (TNF-alpha) on expression of these molecules on four uveal melanoma cell lines. The in vitro integrin expression was quite variable. The alpha V and beta 1 subunits were expressed on all cell lines, and none of the cell lines showed any alpha 3, beta 2, or beta 4 expression. Other integrin subunits showed a more variable pattern. ICAM-1 and CD44 were strongly expressed on all cell lines. IFN-alpha, IFN-gamma, and TNF-alpha upregulated alpha 1, alpha 2, and alpha 3 expression, and did not alter alpha 4, alpha 5, alpha 6, beta 2, alpha v beta 3, and beta 4 expression. The effects on alpha V and alpha V beta 5 were variable. ICAM-1 was upregulated by IFN-gamma and TNF-alpha, but not by IFN-alpha. Cytokine treatment hardly changed CD44 expression. In one case a comparison was made between expression on cultured cells and on tissue sections of the tumour of origin. Differences in expression were observed for the integrin subunits alpha 2, alpha 3, and alpha 5. This study shows that integrins and ICAM-1 expression on uveal melanoma cells in vitro are susceptible to cytokine treatment, but that the effects on integrin expression are cytokine and cell line dependent. Furthermore, some differences in integrin expression between cells in vivo and in vitro exist.

Cryoultramicrotomy↗

PubMed2004

Leukocyte adhesion deficiency III: a group of integrin activation defects in hematopoietic lineage cells.

PURPOSE OF REVIEW: In the last 2-3 years our understanding of leukocyte adhesion cascades has increased, mainly in defining new pathways by which integrin activation occurs on circulating leukocytes recruited to sites of inflammation. While defects in the integrin structure (leukocyte adhesion deficiency (LAD) I) and in the selectin glycoprotein ligand biosynthesis (LAD II) have been described in the past few decades, a newly recognized defect in the activation of integrins (LAD III) was only recently delineated. The clinical manifestations and molecular basis of this syndrome and related cases will be reviewed. RECENT FINDINGS: While in LAD I and II the defect in the adhesion cascade is restricted to leukocytes, all four cases of LAD III described to date also had defects in platelet aggregation. These patients suffered from recurrent bacterial infections and a severe bleeding tendency. All cases were reported to have activation defects in all major integrin subfamily members expressed in circulating leukocytes and platelets. In one case there was a defect in Rap1, which is a crucial protein in the inside-out and outside-in (ligand-induced) signaling underlying integrin activation mainly by cytokines. In this case, both chemokines and cytokines were unable to activate Rap1 leading to severe adhesive defects analyzed in vitro. SUMMARY: While in LAD I and II the primary genetic defect is known, in the newly described LAD III the primary event leading to the defect is still unknown, despite a clear biochemical defect in Rap1 activation. The molecular basis or the defect in integrin activation may be different in the various cases described so far. It seems logical, however, to assume that in all reported cases, a key component of inside-out signaling to integrins activation is involved.

Biotransformation↗

PubMed2005

Hypoxia activates MAPK activity in rat nucleus pulposus cells: regulation of integrin expression and cell survival.

OBJECTIVE: The aim of the present study was to investigate whether activation of MAPK subtypes ERK and p38 influences integrin expression and promotes nucleus pulposus cell survival in hypoxia. SUMMARY OF BACKGROUND DATA: We have recently shown that in a low oxygen environment, rat nucleus pulposus cells activate phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. However, the role of these signaling pathways in regulating cell matrix interactions is not known. METHODS: Rat nucleus pulposus cells were cultured in hypoxia (2% O2) or normoxia (20% O2). Western blotting and kinase assay were used to analyze expression of MAPK signaling molecules. Cell attachment to collagen was studied using an adhesion assay, whereas flow cytometry and RT-PCR were performed to quantify integrin receptor expression. RESULTS: In a hypoxic environment (2% O2), rat nucleus pulposus cells showed a persistent phosphorylation of p38 and ERK proteins; pERK catalyzed the phosphorylation of Elk1-Gst fusion protein. When ERK activity was blocked, cell adhesion to Type II collagen, one of the major extracellular matrix proteins in the nucleus pulposus tissue, was impaired. A similar inhibitory effect on collagen adhesion was observed when nucleus pulposus cells were treated with an antibody to alpha2 integrin. Furthermore, when ERK activity was inhibited, there was a decrease in alpha2 integrin mRNA expression. In contrast to ERK, inhibition of p38 activity did not modulate alpha2 integrin subunit mRNA expression. Likewise, inhibition of ERK, but not p38, resulted in downregulation of nucleus pulposus alpha2 integrin protein levels and blocked cell survival in hypoxia. CONCLUSIONS: Hypoxia activated MAPK signaling pathway activity in nucleus pulposus cells. ERK, but not p38, regulated alpha2 integrin expression and cell survival.

Animals↗

PubMed2005

Human alphavbeta3 integrin potency and specificity of TA138 and its DOTA conjugated form (89)Y-TA138.

The present study was undertaken to define the alphavbeta3-binding potency and specificity of TA138, a nonpeptide integrin antagonist, and its conjugated form, 89Y-TA138. Various integrin-specific binding and functional assays as well as cell-adhesion assays were used to determine the potency and integrin specificity for TA138 and 89Y-TA138. Both TA138 and 89Y-TA138 inhibited alphavbeta3-mediated [125I]echistatin binding to 293-beta3-transfected cells, with IC50 values of 0.046 and 0.059 microM, respectively, and IC50 values of 0.012 and 0.018 microM, respectively, in inhibiting an alphavbeta3 integrin-mediated 293-beta3-transfected cell adhesion to fibrinogen. TA138 inhibited human umbilical vein endothelial cell adhesion to fibrinogen, with an IC50 value of 0.052 +/- 0.006 microM. Both TA138 and 89Y-TA138 demonstrated a relatively high degree of specificity for human alphavbeta3 integrin as compared with other human integrins, including alphavbeta5, alphaIIbbeta3, and alpha5beta1 (IC50 > 10 microM). Both 89Y-TA138 and TA138 demonstrated comparable alphavbeta3 affinity and specificity as compared with other closely related human integrins such as alphavbeta5, alphaIIbbeta3, or alpha5beta1.

Cell Adhesion↗

PubMed2004

Alpha V integrin prolongs collagenase production through Jun activation binding protein 1.

Robust expression of alphav integrin and matrix metalloproteinase 1 (MMP1) plays an important role in cancer metastasis and wound healing. A patient with an abnormal scar that appeared stretched and thinned out was found to have fibroblasts that overexpressed alphav integrin; therefore, a relationship between alphav integrin expression and MMP1 production was sought. A yeast 2 hybrid screen revealed alphav integrin interacts with jun activation binding domain-1 (JAB1). Mesenchymal-derived cells were transfected with the alphav integrin gene and incorporated into collagen lattices. Transfected cells maximally contracted collagen lattices beginning on day 5, whereas control transfected cells did not contract lattices. Late-phase collagen lattice contraction was inhibited by a pan-MMP inhibitor, BB4. Overexpression of alphav correlated with enhanced MMP1 transcription, as determined by a luciferase assay (P < or = 0.05). Diminution of JAB1 with JAB1 antisense abolished alphav integrin up-regulation of MMP1. We conclude alphav integrin signals through JAB1 to prolong MMP1 production and that this signaling pathway in fibroblasts may lead to abnormal scarring.

COP9 Signalosome Complex↗

PubMed2006

In vivo beta1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines.

Integrins are heterodimeric adhesion receptors associated with bidirectional signaling. In vitro studies support a role for the binding of evolutionarily conserved tyrosine motifs (NPxY) in the beta integrin cytoplasmic tail to phosphotyrosine-binding (PTB) domain-containing proteins, an interaction proposed to be dynamically regulated by tyrosine phosphorylation. Here we show that replacement of both beta1 integrin cytoplasmic tyrosines with alanines, resulting in the loss of all PTB domain interaction, causes complete loss of beta1 integrin function in vivo. In contrast, replacement of beta1 integrin cytoplasmic tyrosines with phenylalanines, a mutation that prevents tyrosine phosphorylation, conserves in vivo integrin function. These results have important implications for the molecular mechanism and regulation of integrin function.

Amino Acid Motifs↗

PubMed1994

Confocal microscopic analysis of integrin expression on the microvasculature and its sprouts in the neonatal foreskin.

Members of the integrin family of adhesion receptors are essential participants in blood vessel growth and remodeling. It is not known which integrins are involved in the initial stages of angiogenesis in vivo. In this study we determined the location of integrins on the blood vessels of a growing tissue, the neonatal foreskin, in which neovascularization is likely to occur. We used the confocal microscope to visually reconstruct vessels from the papillary dermis of the foreskin and to identify potential sprouts as narrow, tapering extensions from these vessels. Blood vessels were initially identified by their positive reaction with antibodies to von Willebrand factor or human platelet endothelial cell adhesion molecule and their negative response to anti-neurofilament antibodies. Later, vessels were identified by their shape and location. We screened vessels with anti bodies to integrin subunits alpha 1, alpha 2, alpha 3, alpha 5, alpha 6, alpha v, beta 1, beta 3 and beta 4. We found that integrin subunits alpha 6 and beta 4 were consistently found along the whole length of capillary loops and extended to the distal ends of presumed sprouts. The alpha 2 and alpha v integrin concentrations, which are normally low in the microvasculature, were increased on the sprouts. alpha 5 was either absent from vessels entirely or more concentrated on the body than on the sprout. alpha 1 was more commonly present on nerves than blood vessels. These studies suggest an important role for the alpha 6 beta 4 integrin in the initial stages of endothelial outmigration during new vessel growth.

Blood Vessels↗

PubMed1992

Expression of integrin alpha 6 beta 4 in junctional epidermolysis bullosa.

The integrin alpha 6 beta 4 is a member of the integrin family of adhesion receptors. The integrin alpha 6 beta 4 is preferentially expressed in stratified squamous epithelia, where it is localized in hemidesmosomes. A reduced number of rudimentary hemidesmosomes is often found in skin from patients with junctional epidermolysis bullosa (JEB). In this study we have investigated the expression of alpha 6 beta 4 in skin specimens of patients with junctional (one non-lethal, two lethal) and dystrophic (two) epidermolysis bullosa, using immunofluorescent (IF) staining with five different monoclonal antibodies against the alpha 6 and beta 4 subunits. The intensity of IF staining of the integrin alpha 6 beta 4 and bullous pemphigoid antigen (BPA) was unreduced along the epidermal basement membrane zone (EBMZ) of all EB patients, compared to that in skin of healthy human controls. However, in the skin of two patients with lethal (Herlitz) JEB, who did not express GB3, IF staining of integrin alpha 6 beta 4 and BPA showed a "stitchy" discontinuous linear pattern along the EBMZ with interruptions at the borders of adjoining basal keratinocytes. The same results were obtained by immunoelectron microscopy. They corresponded with freeze-induced partial cell detachment from the basement membrane at the ultimate baso-lateral edge of the basal keratinocytes in lethal JEB skin. The basal lamellipodia at that location almost completely lacked tonofilaments and hemidesmosomes. Furthermore, in JEB there was a split between the intra- and extracellular epitopes of the integrin alpha 6 beta 4 receptor, whereas the integrin remains intact in salt-split skin. This suggests that the defect is in alpha 6 beta 4 itself or perhaps its ligand.

Adult↗

PubMed1993

Alterations of integrin expression in human lung cancer.

Integrins are cell-surface receptors which are involved in cell-matrix and/or cell-cell adhesion. They have been suggested to play a role in tumor invasion and metastasis. We examined the expression of various integrin subunits in normal and cancer cells of the lung using 33 human lung cancer cell lines as well as 6 lung cancer samples from which tumor cell lines could be established. This study clearly demonstrated that changes in the expression of certain integrins occur frequently in lung cancer, especially in small cell lung cancer. Loss of the alpha 1 subunit of the beta 1 integrin family appears to be the most prominent change, although loss of other integrin subunits such as alpha 2 or emergence of some integrin subunits such as alpha v can also be observed. These results suggest that changes in integrin expression may contribute to the invasive and/or metastatic behavior of lung cancer.

Carcinoma, Small Cell↗

PubMed2004

Integrin signaling in inflammatory and neuropathic pain in the rat.

Many painful conditions are associated with alterations in the extracellular matrix (ECM) of affected tissues. While several integrins, the receptors for ECM proteins, are present on sensory neurons that mediate pain, the possible role of these cell adhesion molecules in inflammatory or neuropathic pain has not been explored. We found that the intradermal injection of peptide fragments of domains of laminin and fibronectin important for adhesive signaling selectively inhibited the hyperalgesia caused by prostaglandin E2 (PGE2) and epinephrine (EPI), respectively. The block of EPI hyperalgesia was mimicked by other peptides containing the RGD integrin-binding sequence. Monoclonal antibodies (mAbs) against the alpha1 or alpha3 integrin subunits, which participate in laminin binding, selectively blocked PGE2 hyperalgesia, while a mAb against the alpha5 subunit, which participates in fibronectin binding, blocked only EPI-induced hyperalgesia. A mAb against the beta1 integrin subunit, common to receptors for both laminin and fibronectin, inhibited hyperalgesia caused by both agents, as did the knockdown of beta1 integrin expression by intrathecal injection of antisense oligodeoxynucleotides. The laminin peptide, but not the fibronectin peptides, also reversibly abolished the longer lasting inflammatory hyperalgesia induced by carrageenan. Finally, the neuropathic hyperalgesia caused by systemic administration of the cancer chemotherapy agent taxol was reversibly inhibited by antisense knockdown of beta1 integrin. These results strongly implicate specific integrins in the maintenance of inflammatory and neuropathic hyperalgesia.

Animals↗

PubMed2004

Expression of integrins and E-cadherin in squamous cell carcinomas of the head and neck.

Integrins and cadherins are cell adhesion molecules suggested to play an important role in malignant progression and tumour differentiation. Our aim was to characterise the pattern of expression and the relations between integrin beta1, beta4, beta6 and E-cadherin and the different histopathological features important when judging tumour differentiation, using a well-defined scoring system. Formalin-fixed paraffin-embedded pre-irradiation biopsies from 85 patients with head and neck squamous cell carcinomas (HNSCC) were stained and evaluated for the expression of integrin beta1, beta4 and beta6 and E-cadherin. The integrins were upregulated in carcinomas compared to the adjacent mucosa and E-cadherin was downregulated. However, differences were found within the tumour: Expression of E-cadherin was lost and the three integrins were upregulated at the tumour borders, compared to central parts of the tumour biopsy. Expression of the integrins did not correlate with tumour or histopathological parameters, whereas expression of E-cadherin was correlated with high degree of keratinisation, high nuclear maturation and few mitoses - factors that characterise well-differentiated carcinomas -and E-cadherin can therefore be considered as a marker of differentiation. Furthermore, loss of adhesion expressed by low E-cadherin and integrin beta4 correlated with the presence of nodal metastases at the time of diagnosis.

Biomarkers, Tumor↗

PubMed1996

Decreased expression of alpha 2 beta 1 integrin in scleroderma fibroblasts.

Systemic scleroderma (SSc) is a complex connective tissue disorder of unknown etiology. In early stages of the disease, fibroblasts are activated to produce large amounts of collagen with subsequent fibrosis. Collagen metabolism of fibroblasts is modulated by their contact with the extracellular matrix (ECM), which involves distinct receptors on the cell surface, mainly belonging to the integrins. We investigated the expression of collagen receptor alpha 2 beta 1 in SSc and normal fibroblasts, since this receptor has been shown to be utilized by fibroblasts for adhesion to and reorganization of collagen I. 9 strains of scleroderma fibroblasts grown as monolayer cultures were first analyzed with respect to their collagen I expression. 6 of these strains were similar to controls "low" producers) and 3 strains showed up to 2-3 x higher levels of collage I mRNA expression ("high" producers). Northern hybridization using a cDNA probe specific for the alpha 2 integrin subunit revealed a decrease of the corresponding mRNA in SSc fibroblasts as compared to controls (75% versus 100%). "High" collagen producing cell strains displayed the lowest values for alpha 2 integrin mRNA. The decrease of alpha 2 integrin subunit expression at the mRNA level in selected fibroblasts was further substantiated by radioimmunoprecipitation using specific mAbs directed against alpha 2 integrin subunit. No significant changes in beta 1 integrin expression could be observed - neither at mRNA nor at the protein level. Our data indicate a correlation between excessive synthesis of collagen and low levels of alpha 2 integrin subunit expression in SSc fibroblasts. Further experiments should clarify whether this observation is a phenomenon specific for scleroderma or whether it reflects an "activated" state of fibroblasts.

Cells, Cultured↗

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