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PubMed2002

Diminished callus size and cartilage synthesis in alpha 1 beta 1 integrin-deficient mice during bone fracture healing.

Integrins mediate cell adhesion to extracellular matrix components. Integrin alpha 1 beta 1 is a collagen receptor expressed on many mesenchymal cells, but mice deficient in alpha 1 integrin (alpha1-KO) have no gross structural defects. Here, the regeneration of a fractured long bone was studied in alpha1-KO mice. These mice developed significantly less callus tissue than the wild-type (WT) mice, and safranin staining revealed a defect in cartilage formation. The mRNA levels of nine extracellular matrix genes in calluses were evaluated by Northern blotting. During the first 9 days the mRNA levels of cartilage-related genes, including type II collagen, type IX collagen, and type X collagen, were lower in alpha1-KO mice than in WT mice, consistent with the reduced synthesis of cartilaginous matrix appreciated in tissue sections. Histological observations also suggested a diminished number of chondrocytes in the alpha 1-KO callus. Proliferating cell nuclear antigen staining revealed a reduction of mesenchymal progenitors at the callus site. Although, the number of mesenchymal stem cells (MSCs) obtained from WT and alpha 1-KO whole marrow was equal, in cell culture the proliferation rate of the MSCs of alpha 1-KO mice was slower, recapitulating the in vivo observation of reduced callus cell proliferation. The results demonstrate the importance of proper collagen-integrin interaction in fracture healing and suggest that alpha1 integrin plays an essential role in the regulation of MSC proliferation and cartilage production.

Aggrecans↗
PubMed2005

Dynamic protein expression patterns during intraoral wound healing in the rat.

Wound healing after cleft palate surgery is often associated with impairment of maxillary growth and dento-alveolar development. Wound contraction and scar tissue formation contribute strongly to these effects. In vitro studies have revealed that fibroblasts isolated during different phases of palatal wound healing show phenotypical differences. They change from a quiescent to an activated state and then partly back to a quiescent state. In this study, we evaluated the existence of fibroblast phenotypes at several time-points during palatal wound healing in the rat. Based on cytoskeletal changes (alpha-sma, vimentin, vinculin), integrin expression (alpha1, alpha2, alpha(v) and beta1) and changes in cellularity, we conclude that phenotypically different fibroblast populations are also present during in vivo wound healing. Alpha-sma and the integrin subunits alpha1 and alpha(v) were significantly up-regulated, and vinculin was significantly down-regulated, at early time-points compared to late time-points in wound healing. These changes point to an activated fibroblast state early in wound healing. Later in wound healing, these activated fibroblasts return only partially to the unwounded situation. These results strongly support the idea that different fibroblast populations with specific phenotypes occur in the course of palatal wound healing.

Actins↗
PubMed2000

Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization.

Integrin alpha1beta1 is a collagen receptor abundantly expressed on microvascular endothelial cells. As well as being the only collagen receptor able to activate the Ras/Shc/mitogen-activated protein kinase pathway promoting fibroblast cell proliferation, it also acts to inhibit collagen and metalloproteinase (MMP) synthesis. We have observed that in integrin alpha1-null mice synthesis of MMP7 and MMP9 was markedly increased compared with that of their wild-type counterparts. As MMP7 and MMP9 have been shown to generate angiostatin from circulating plasminogen, and angiostatin acts as a potent inhibitor of endothelial cell proliferation, we determined whether tumor vascularization was altered in the alpha1-null mice. Tumors implanted into alpha1-null mice showed markedly decreased vascularization, with a reduction in capillary number and size, which was accompanied by an increase in plasma levels of angiostatin due to the action of MMP7 and MMP9 on circulating plasminogen. In vitro analysis of alpha1-null endothelial cells revealed a marked reduction of their proliferation on both integrin alpha1-dependent (collagenous) and independent (noncollagenous) substrata. This reduction was prevented by culturing alpha1-null cells with plasma derived from plasminogen-null animals, thus omitting the source from which to generate angiostatin. Plasma from tumor-bearing alpha1-null animals uniquely inhibited endothelial cell growth, and this inhibition was relieved by the coaddition of either MMP inhibitors, or antibody to angiostatin. Integrin alpha1-deficient mice thus provide a genetically characterized model for enhanced angiostatin production and serve to reveal an unwanted potential side effect of MMP inhibition, increased tumor angiogenesis.

Angiostatins↗
PubMed1999

Collagen integrin receptors regulate early osteoblast differentiation induced by BMP-2.

Studies in several cell types indicate that the actions of integrin receptors for extracellular matrix and receptors for growth factors are synergistic in regulating cellular differentiation and function. We studied the roles of the alpha1beta1 and alpha2beta1 integrin collagen receptors in regulating the differentiation of 2T3 osteoblastic cells in response to bone morphogenetic protein (BMP)-2. The immortalized 2T3 cell line was established from the calvaria of mice transgenic for a BMP-2 promoter driving SV40 T-antigen. These cells require exogenous BMP-2, as well as ascorbic acid and beta-glycerolphosphate, for expression of a mature osteoblast phenotype and formation of a mineralized matrix. To determine how integrin receptors for collagen-I affect BMP-2 signaling, function-perturbing anti-rat alpha1 and/or alpha2 integrin subunit, or anti-type I collagen (Col-I), antibodies were added to human recombinant (hr)BMP-2-treated 2T3 cultures at confluence (C0) or at 4 or 8 days postconfluence (C4, C8). After 4 days of exposure to the antibodies, cultures were assayed for alkaline phosphatase (ALP) mRNA levels and enzyme activity and for cAMP production in response to parathyroid hormone. Addition of anti-collagen-I or both anti-integrin-alpha1 and -alpha2 antibodies to C0 cultures blocked expression of these early osteoblast markers by more than 90%, and also blocked mineralization (0.5-1.8% control) of these cells. In all cases, adding anti-alpha1 or anti-alpha2 antibodies separately produced partial effects, while their combined effect approached that of anti-collagen-I. When antibodies were added to more differentiated 2T3 cells, the inhibitory effects decreased. 2T3 cells carrying constitutively active BMP receptor (caBMPR-IB) showed elevated ALP activity without hrBMP-2; this constitutive activity was also suppressed by alpha1 and alpha2 integrin antibodies and by anti-Col-I antibody. Together, our data suggest that a signal(s) from collagen integrin receptors regulates the response to BMP downstream of BMPR-IB and upstream of the regulation of ALP mRNA and other early markers of osteoblast differentiation.

Alkaline Phosphatase↗
PubMed2005

Role of integrin alpha1beta1 in the regulation of renal medullary osmolyte concentration.

The mechanism by which cells sense extracellular tonicity and trigger the accumulation of protective organic osmolytes is poorly understood. It has been proposed that changes in cell volume following alteration of extracellular toncity are important initiators of signaling events that lead to osmolyte accumulation. Because the extracellular matrix receptors integrins are linked to the cytoskeleton and can transduce signals that alter cell behavior, we investigated the role of these receptors in the modulation of osmolyte accumulation in the kidney medulla under different osmotic conditions. We show that integrin alpha1-null mice have impaired ability to accumulate organic osmolytes in the inner medulla due to altered signaling and decreased induction of osmolyte transporters or aldose reductase gene transcription. Utilizing inner medullary collecting duct cells, we demonstrate that the lack of integrin alpha1beta1 results in an impaired ability to induce the tonicity enhancer-binding protein TonEBP under hypertonic conditions. Furthermore, under the same conditions, integrin alpha1-null cells show prolonged ERK1/2 phosphorylation and decreased inositol uptake compared with control cells. The reduction of inositol uptake is significantly reversed by treatment with the MEK inhibitor PD-98059. Finally, integrin alpha1-null mice develop morphological changes of early tubular necrosis and increased apoptosis of renal medullary cells following dehydration. Together, these results show that integrin alpha1beta1 is an important mediator of the compatible osmolyte response in the medulla of the mammalian kidney.

Aldehyde Reductase↗
PubMedDate not supplied

A mandibular propulsive appliance modulates collagen-binding integrins distribution in the young rat condylar cartilage.

We have previously shown that a mandibular propulsive appliance (MPA) stimulates cell proliferation and the synthesis of growth factors in the rat condylar cartilage. The aim of this study was to evaluate the effects of a MPA in the distribution of the integrin subunits alpha1 and alpha2 in this cartilage. Twenty eight days-old male Wistar rats were divided into treated (T) and age-matched control groups (C). Treated rats wore the appliance during 3, 5, 7, 9, 11, 15, 20, 30 and 35 days. The condyles were fixed, decalcified and paraffin-embedded. The distribution of alpha1 and alpha2 was studied by immunohistochemistry. Alpha1 distribution was uniform along the cartilage, increasing in 48 days-old rats (C20). Treated animals anticipated this increase to the age of 36 days (T9). The number of alpha2-positive cells was increased in C9 in the anterior condylar region, in C9 and C20 in the middle region and showed no differences in the posterior region. The MPA apparently abolished all variations, leading to a single increase at T30 in all regions. These results suggest that integrins containing the alpha1 and alpha2 subunits are modulated by forces promoted by the MPA, participating of the biological response to this therapy.

Animals↗
PubMed2002

Antiphospholid antibodies regulate the expression of trophoblast cell adhesion molecules.

OBJECTIVE: To examine the effect of antiphospholipid antibodies on trophoblast expression of adhesion molecules. DESIGN: Primary cytotrophoblast cell cultures. SETTING: Department of Obstetrics and Gynecology, Catholic University, Rome, Italy. PATIENT(S): Five normal pregnant women underwent uncomplicated vaginal delivery at 36 weeks of gestation. INTERVENTION(S): IgG antibodies were isolated from a patient with antiphospholipid syndrome and from a normal control subject, using protein-G Sepharose columns. Cytotrophoblast cells were dispersed in bicarbonate buffer containing trypsin and DNAse I. MAIN OUTCOME MEASURE(S): We investigated the effects of antiphospholipid antibodies on trophoblast adhesion molecules (alpha1 and alpha5 integrins, E and VE cadherins), both at the protein and mRNA levels. RESULT(S): The alpha1 and alpha5 integrins were present in trophoblast cells from 24 hours of culture. Treatment with IgG that were obtained from the patient with antiphospholipid syndrome significantly decreased alpha1 integrin and increased alpha5 integrin at both the mRNA and protein levels. Furthermore, IgG with antiphospholipid antibodies activities induced VE-cadherin down-regulation and the E-cadherin up-regulation at protein and mRNA levels compared with control IgG or untreated cells. CONCLUSION(S): The results suggest that the inadequate trophoblastic invasion, induced by antiphospholipid antibodies, can be the result of abnormal trophoblast adhesion molecules expression.

Antibodies, Antiphospholipid↗
PubMed2002

Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis.

Angiogenesis is essential for tumor growth and blocking this process might be a valid tool for the control of cancer growth. We showed previously that tumor angiogenesis in integrin alpha1-null mice is reduced compared to that of wild type animals and that over-expression of matrix metalloproteinase 9 (MMP-9) in the alpha1-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from circulating plasminogen was implicated in the mechanism of tumor inhibition. Our findings suggested that secretion of excess MMPs generates inhibitors of endothelial cell proliferation, including but not necessarily limited to angiostatin, resulting ultimately in auto-inhibition of angiogenesis. Thus MMP inhibitors used as anti-tumor drugs might in fact cause a paradoxical increase in tumor angiogenesis and tumor growth. In order to determine whether MMP-9 expression was directly involved in the regulation of tumor growth, we specifically inhibited or enhanced MMP-9 synthesis in vitro and in vivo, and subsequently analysed primary endothelial cell proliferation and angiostatin synthesis, as well as tumor vascularization and development. We provide evidence that reduction of plasma levels of MMP-9 in either normal or integrin alpha1-null mice leads to decreased synthesis of angiostatin and consequent increased tumor growth and vascularization. In contrast, specifically enhancing MMP-9 expression in vivo caused a reduction in tumor vascularization. These findings are the opposite to other studies suggesting a pro-tumorigenic role for MMP-9, and may account for some of the recently observed failures of anti MMP therapy in tumor treatment.

Angiostatins↗
PubMed1997

The platelet reactivity of synthetic peptides based on the collagen III fragment alpha1(III)CB4. Evidence for an integrin alpha2beta1 recognition site involving residues 522-528 of the alpha1(III) collagen chain.

The platelet-reactive collagen III-derived fragment alpha1(III)CB4 has been synthesized as seven overlapping peptides, each as a homotrimeric triple-helical species covalently linked at the C terminus. Additional Gly-Pro-Hyp triplets were introduced at each end of the peptide sequence to ensure a stable triple-helical conformation at 20 degrees C, the temperature at which cell reactivity was measured. A Cys-containing triplet was included at each end to allow intermolecular cross-linking. All seven peptides in triple-helical, cross-linked form were able to cause platelet aggregation. Peptide 6, the most reactive species, was more aggregatory than collagen fibers. Platelet adhesion occurred to all peptides immobilized on plastic in monomeric form. Adhesion was integrin alpha2beta1-independent except in the case of peptide 6, adhesion to which was partially reduced by anti-integrin alpha2beta1 monoclonal antibodies. The presence of an alpha2beta1 recognition site in peptide 6 was confirmed using HT 1080 cells, which express alpha2beta1 as their major or sole collagen receptor. HT 1080 adhesion to both peptide 6 and collagen was strongly inhibited by anti-integrin alpha2beta1 monoclonal antibodies. These cells did not adhere to any of the other peptides. Comparison of the structure of peptide 6 with that of adjacent peptides indicates that the sequence Gly-Gly-Pro-Hyp-Gly-Pro-Arg, residues 522-528 of the collagen alpha1(III) chain, represents the minimum structure required for the recognition of alpha2beta1. Our findings support the view that the collagen triple helix possesses an intrinsic platelet reactivity that can be expressed independently of integrin alpha2beta1 and the precise level of which is governed by the exact nature of the primary sequence. Sequences such as those recognizing alpha2beta1 may potentiate the activity, whereas others may have the opposite effect.

Amino Acid Sequence↗
PubMed2006

Expression of alpha 1 and beta 3 integrins subunits in the endometrium of patients with tubal phimosis or hydrosalpinx.

OBJECTIVE: To determine the expression of alpha1 and beta3 integrin subunit on the endometrium of infertile patients with hydrosalpinx and infertile patients with tubal phimosis. DESIGN: Case-control study. SETTING: Tertiary medical center. PATIENT(S): Infertile patients with radiologic or laparoscopic diagnosis of hydrosalpinx (n = 11) or tubal phimosis (n = 12) as the only cause of infertility, and fertile controls (n = 17). INTERVENTION(S): Immunohistochemical analysis of alpha1 and beta3 integrin subunits was performed on endometrial biopsies obtained during the implantation window. MAIN OUTCOME MEASURE(S): Histologic score (HSCORE) on luminal and glandular endometrium of the patients with hydrosalpinx or tubal phimosis and the normal fertile controls. RESULT(S): The median (+/-SEM) HSCORE for beta3 subunit expression in endometrial glands was 0.39 +/- 0.23 and 0.42 +/- 0.18 for tubal phimosis and hydrosalpinx, respectively, and 1.74 +/- 0.26 for fertile controls. The median HSCORE for beta3 subunit expression in luminal epithelium for tubal phimosis, hydrosalpinx, and fertile controls was 0.07 +/- 0.06, 0.21 +/- 0.18, and 1.03 +/- 0.31, respectively. No statistical difference was observed on the expression of alpha1 integrin subunit expression between the three groups. CONCLUSION(S): The endometrial expression of beta3 integrin subunit is reduced in the presence of tubal phimosis or hydrosalpinx, during the window of implantation.

Adult↗
PubMed2005

Human alpha1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 integrin.

Human noncollagenous domain 1 of the alpha1 chain of type IV collagen [alpha1(IV)NC1], or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo; however, the mechanisms involved are not known. In the present study we demonstrate that human alpha1(IV)NC1 binds to alpha1beta1 integrin, competes with type IV collagen binding to alpha1beta1 integrin, and inhibits migration, proliferation, and tube formation by ECs. Also, alpha1(IV)NC1 pretreatment inhibited FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in ECs but had no effect on the PI3K/Akt pathway. In contrast, alpha1(IV)NC1 did not affect proliferation, migration, or the activation of FAK/c-Raf/MEK1/2/p38/ERK1 MAPK pathway in alpha1 integrin receptor knockout ECs. Consistent with this, alpha1(IV)NC1 elicited significant antiangiogenic effects and tumor growth inhibition in vivo but failed to do the same in alpha1 integrin receptor knockout mice. This suggests a highly specific, alpha1beta1 integrin-dependent antiangiogenic activity of alpha1(IV)NC1. In addition, alpha1(IV)NC1 inhibited hypoxia-induced expression of hypoxia-inducible factor 1alpha and VEGF in ECs cultured on type IV collagen by inhibiting ERK1/2 and p38 activation. This unravels a hitherto unknown function of human alpha1(IV)NC1 and suggests a critical role for integrins in hypoxia and hypoxia-induced angiogenesis. Collectively, the above data indicate that alpha1(IV)NC1 is a potential therapeutic candidate for targeting tumor angiogenesis.

Angiogenesis Inhibitors↗
PubMed2000

Integrin expression by primary and immortalized human chondrocytes: evidence of a differential role for alpha1beta1 and alpha2beta1 integrins in mediating chondrocyte adhesion to types II and VI collagen.

OBJECTIVE: Chondrocytes have been shown to express beta1-containing integrins both in vitro and in situ, but their role in regulating chondrocyte function is poorly understood. The objective of this study was to determine how the relative expression of different integrins may be modulated in relation to the differentiated state and proliferative capacity of the chondrocyte. DESIGN: Integrin expression by four different cell lines of human chondrocytes immortalized with Simian virus 40 large T-antigen (SV40-TAg) was studied and compared to primary chondrocytes. Differences in alpha1 and alpha2 integrin subunit expression were utilized to further study the role of these integrins in mediating adhesion to types II and VI collagen. RESULTS: The overall cell-surface levels of beta1-containing integrins were higher on all four immortalized cell lines which expressed over 10-fold higher levels of alpha2 and alpha3 integrin subunits compared to primary cells. However, primary cells expressed higher levels of the alpha1 integrin subunit which was not expressed by T/C28a4 cells and expressed at variable and lower levels in the other lines. Levels of the alpha3 integrin subunit were significantly greater on the highly proliferative juvenile costal chondrocyte lines (T/C-28a4, C-2812, and C-20a4) compared to primary articular chondrocytes and tsT/AC-62 cells which were derived from adult articular chondrocytes. Expression of alpha5 was similar among primary cells and cell lines except on C-20/A4 cells which had an average of over 4-fold higher levels. None of the primary or immortalized chondrocytes tested expressed significant levels of alpha4. Cell adhesion assays revealed that both alpha1beta1 and alpha2beta1 could serve as chondrocyte adhesion receptors for types II and VI collagen. In cell lines expressing both integrins, alpha1beta1 was the preferential receptor for type VI collagen while alpha2beta1 was the preferential receptor for type II collagen. Rather than inhibiting adhesion, incubation with the alpha3 blocking antibody P1B5 increased adhesion of C-28/12 cells to both fibronectin and type II collagen by 67% and 100% respectively. CONCLUSIONS: Immortalization with SV40-TAg results in altered integrin expression by chondrocytes. Changes in the relative levels of alpha1, alpha2, and alpha3 subunits may significantly alter the manner in which chondrocytes interact with types II and VI collagen in the extracellular matrix.

Adult↗
PubMed2006

Characterization of the integrin receptor subunit profile in the mammalian sclera.

PURPOSE: During the increased eye growth that results in myopia, the sclera undergoes biochemical and biomechanical remodeling. The cell surface integrin receptor family has important roles during tissue remodeling, regulating the extracellular matrix environment and cellular biomechanical properties. As integrin receptors may have a role in remodeling during myopia, this study detailed subunit gene expression in the mammalian sclera. METHODS: Several tissues, including sclera, were isolated from the tree shrew, a mammalian model used in eye growth studies. Total RNA was purified, reverse transcribed and primers for the alpha- and beta-integrin subunits were designed to the published human sequence in areas of high inter-species homology. PCR was used to amplify products of predetermined size and all tree shrew integrin subunits were sequenced to confirm their identity. Multiple PCR conditions were used to identify the scleral integrin subunits, and positive control tissues were included to reduce the possibility of false negative results. RESULTS: Integrin PCR products corresponding to the beta1-, beta4-, beta5-, and beta8-integrin subunits and the alpha-integrin subunits, alpha1-6-, alpha9-11- and alphav-integrin were identified in the sclera and in scleral fibroblast cultures. The respective sequences showed a high identity (>81%) to their human counterparts. The beta2-, beta3-, beta6-, beta7-, alpha7-, and alpha8-integrin subunits were not detected in tree shrew scleral samples, despite being present in the respective positive controls. Association of the 4 beta-integrin subunits with the 10 alpha-integrin subunits suggests that the mammalian sclera is capable of expressing 13 of the 24 identified integrin receptors. CONCLUSIONS: This is the first systematic description of the integrin subunit expression profile in the sclera. Due to the multiple roles of integrin receptors during tissue remodeling, the identification of these scleral integrins is an important preliminary step in determining the role of these receptors during normal eye growth and myopia development.

Animals↗
PubMed2002

Influence of anti-CD49f and anti-CD29 monoclonal antibodies on mitotic activity of epithelial cells (HaCaT) and gingival fibroblasts in vitro.

A major complication in the treatment of periodontitis marginalis is the reepithelization of periodontal defects inhibiting collagen fiber attachment and periodontal regeneration. In this study we investigated the possibility of a molecular blockade of epithelial mitosis in vitro. Monoclonal antibodies against the VLA-6 laminin receptor subunit alpha6 interrupted interactions between epithelial cells (HaCaT cells) and their extracellular matrix and thus resulted in reduction of proliferation rates by more than 50%. The same effect was observed with anti alpha1-antibodies. In contrast, collagen-producing and -secreting gingival fibroblasts, which play an important role in periodontal regeneration, remained unaffected by the applied anti alpha6 antibodies. Correspondingly, these cells were found to lack VLA-6 laminin receptors. Selective molecular inhibition of epithelial proliferation and apical migration by monoclonal anti alpha6 antibody application may provide an adjuvant periodontitis therapy resulting in an enhanced periodontal regeneration.

Antibodies, Monoclonal↗
PubMed1998

Integrin expression in normal and out-of-phase endometria.

Integrins have recently been proposed as having a major role in endometrial receptivity. Different patterns of integrin expression have been described during the normal endometrial cycle, and the co-expression of several integrins, mainly alpha1, alpha4 and beta3 has been considered as specific to the 'window of implantation'. In the present study 55 infertile patients underwent two endometrial biopsies during a single menstrual cycle. An early biopsy was done on postovulatory days 6-8, and a late biopsy was performed on postovulatory days 10 to 12. Histological dating as well as immunohistochemical evaluation of alpha1, alpha4, beta1, beta3, beta5, alpha(v)beta3 integrin expression and oestrogen and progesterone receptors were determined in all endometrial biopsies. Oestradiol and progesterone serum concentrations in serum were evaluated on the same days of the endometrial samplings. Nine out of the 55 midluteal biopsies (16.4%) showed out-of-phase endometria, but all biopsies were in phase in the late luteal phase. Differences in integrin expression between in- and out-of-phase biopsies were observed only for alpha(v)beta3 integrin glandular expression during the midluteal phase. Alpha(v)beta3 integrin glandular expression was found in all late luteal phase biopsies. Alpha(v)beta3 expression was closely correlated with histological maturation of the endometrium appearing suddenly at postovulatory day 6-7 and being expressed by all endometria dated as postovulatory day > or = 8, irrespective of midluteal endometrial biopsies being in phase or out of phase. No differences in integrin expression were detected between patients with or without endometriosis or between patients who became spontaneously pregnant and those who did not. In conclusion, further studies are necessary before patterns of integrin expression may offer an alternative to predict uterine receptivity and implantation potential.

Adult↗
PubMed2004

Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype.

Cytotrophoblasts of the anchoring villi convert during human placentation from a transporting epithelium to an invasive, extravillous phenotype that expresses a distinct repertoire of adhesion molecules. Developing extravillous trophoblasts accumulate heparin-binding EGF-like growth factor (HB-EGF), a multifunctional cytokine, which binds HER1 and HER4 of the human EGF receptor (HER/ErbB) family. HB-EGF is downregulated in placentae of women with preeclampsia, a disorder associated with deficient trophoblast invasion, raising important questions about its physiological impact on cytotrophoblasts. Addition of HB-EGF during explant culture of first-trimester chorionic villi enhanced extravillous trophoblast differentiation and invasive activity. Using a first-trimester human cytotrophoblast line, the potential for autocrine and paracrine regulation of the developing trophoblast was established based on the expression of all four HER isoforms, as well as HB-EGF and related growth factors. HB-EGF did not alter proliferation, but initiated extravillous differentiation, with decreased alpha6 integrin expression, increased alpha1, and elevated cell migration. Function-blocking antibodies against EGF family members reduced basal cell motility and antibody inhibition of either HER1 or HER4 ligation prevented HB-EGF-induced integrin switching. We conclude that HER-mediated autocrine and paracrine signaling by HB-EGF or other EGF family members induces cytotrophoblast differentiation to an invasive phenotype.

Animals↗
PubMed1998

Integrin expression in developing smooth muscle cells.

We studied the specific expression patterns and distributions of alpha1 and beta1 integrin subunits, the major cell adhesion receptors in smooth muscle, in developing smooth muscle cells from 16-, 18-, and 20-day embryonic gizzards and from 1- and 7-day post hatch chick gizzards by SDS-PAGE, immunoblotting, and immunoelectron microscopy. Antibodies raised against alpha1 and beta1 integrins isolated from avian gizzards were used as probes. Gels and blots showed that the amount of alpha1 and beta1 integrins increased as age increased, with major increases at 1 and 7 days post hatch. Image analysis of immunoelectron micrographs demonstrated that statistically significant labeling increases occurred between embryonic Days 16 and 18, between embryonic Day 20 and 1 day post hatch, and between 1 day and 7 days post hatch. Immunolabeling with both anti-alpha1 and anti-beta1 integrin was prominent at membrane-associated dense plaques (MADPs) and at filament anchoring regions at cell ends. This indicates that alpha1 and beta1 integrin expression coincides temporally with the intracellular proliferation and reorientation of myofilaments. The similarity in distribution patterns of alpha1 and beta1 integrins during development suggests that the two integrin subunits are synchronously expressed during development and do not appear sequentially. (J Histochem Cytochem 46:119-125, 1998)

Animals↗
PubMed2006

Expression of collagen-binding integrin receptors in the mammalian sclera and their regulation during the development of myopia.

PURPOSE: The sclera has a collagen-rich extracellular matrix that undergoes significant biochemical and biomechanical remodeling during myopic eye growth. The integrin family of cell surface receptors play critical roles in extracellular matrix and biomechanical remodeling in connective tissues. This study identified the major collagen-binding integrin receptors in the mammalian sclera and investigated their mRNA expression during the development of and recovery from experimental myopia. METHODS: The presence of the alpha1, alpha2, and beta1 integrin subunits was examined by using tree-shrew-specific primers and RT-PCR. Scleral expression of alpha1beta1 and alpha2beta1 receptor proteins was further investigated by using Western blot analysis and immunocytochemistry. Myopia was induced monocularly by occluding pattern vision and scleral tissue collected after 24 hours and 5 days. In a subset of the 5-day treatment group, vision was restored for 24 hours before tissue was isolated. Total RNA was extracted, and integrin subunit expression levels were assessed with quantitative real-time PCR. RESULTS: The presence of the major collagen-binding integrin subunits alpha1, alpha2, and beta1 was confirmed by RT-PCR in both scleral tissue and cultured scleral fibroblasts. Both the alpha1 and alpha2 integrin subunit proteins were identified in tree shrew scleral tissues, and integrin receptor expression was localized to scleral fibroblast focal adhesions. After only 24 hours of myopia induction, a time when no structural elongation has occurred, significant decreases were observed in the expression of the alpha1 (-36%) and beta1 (-44%) integrin subunits. After 5 days of myopia induction, alpha1 integrin expression had returned to baseline levels, whereas the alpha2 subunit showed a significant decrease in expression (-52%). The 5-day integrin profiles were maintained during recovery from the induced myopia, with only alpha2 integrin showing a statistically significant relative decrease in expression (-41%). CONCLUSIONS: The mammalian sclera expresses the major collagen-binding integrin subunits. The alpha1 and beta1 subunit expression was decreased early during the development of myopia, whereas the regulation of alpha2 integrin occurred at a later time point. The differential regulation of alpha1beta1 and alpha2beta1 during the development of myopia may reflect specific roles for these receptors in the scleral extracellular matrix and biomechanical remodeling that accompanies myopic eye growth.

Animals↗