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At least 793 records · Page 44Linked to original sources
PubMed1996

Glucose modulates growth of gingival fibroblasts and periodontal ligament cells: correlation with expression of basic fibroblast growth factor.

Diabetes mellitus is a systemic disease with profound effects on oral health and periodontal wound healing. Uncontrolled diabetes adversely affects surgical wound healing and is often associated with abnormal proliferation of fibroblasts, excessive angiogenesis and poor bone regeneration. Human gingival fibroblasts and periodontal ligament cells from both diabetics and non-diabetics were evaluated for growth responses following culture in 20 mM glucose, a concentration compatible with blood glucose levels in uncontrolled diabetics. Gingival fibroblasts derived from 9 non-diabetic patients and 3 insulin-dependent diabetics either proliferated or showed little change of growth in elevated glucose. Enhanced proliferation was observed following 1 wk of culture in glucose. Growth of periodontal ligament cells from 5 non-diabetic patients was inhibited by 20 mM glucose. Fibroblasts that were markedly growth stimulated were probed for expression of basic fibroblast growth factor (bFGF) using a reverse-transcribed polymerase chain reaction (RT-PCR). Results indicate that fibroblasts exhibiting the greatest increase in growth in response to high glucose also exhibited increased expression of bFGF. No changes were observed in mRNA expression for platelet-derived growth factor-AA, platelet-derived growth factor-BB, insulin-like growth factor and transforming growth factor-beta 1. Mitogenic effects induced by the cytosol of fibroblasts exhibiting increases of growth in 20 mM glucose were abrogated by neutralizing antibodies to bFGF. In addition, some periodontal ligament cells that were growth inhibited by high glucose had reduced expression of bFGF. These data suggest that bFGF may play a role in the abnormal wound healing associated with periodontal surgery of uncontrolled diabetics.

Antibodies↗
PubMed1997

Immunolocalization of platelet-derived growth factor A and B chains and PDGF-alpha and beta receptors in human gingival wounds.

Platelet-derived growth factor (PDGF) is a polypeptide growth factor which has been implicated as a major mitogen involved in wound healing. The PDGF appears to promote periodontal regeneration; however, its distribution in gingival tissues is not known and how it participates in gingival wound healing is unclear. Using highly specific antibodies we have studied the distribution of PDGF A and B chains and alpha- and beta-PDGF receptors in healing human gingival wounds. Wounds were created by making a 0.75 mm deep incision in the papilla and healthy gingiva and biopsies were obtained from the same site after 8 h and 1, 3, 7, 14 and 21 d. Frozen sections were immunostained with affinity purified antibodies. The results showed that both epithelium and fibrin clot manifested positive immunostaining for anti-PDGF-A and B-chain antibodies. Staining was present in unwounded and wounded epithelia, and in the fibrin clot it appeared to be more intense for the PDGF-A chain. Blood vessels in connective tissue were also positive while other areas were largely negative. No significant staining was detectable in healthy tissues for anti-PDGF-alpha or -beta receptor antibodies. However, the wound site began to manifest positive immunostaining fro anti-beta-receptor antibody after 3 d of healing, became maximal at 7 d, and then decreased. Our data indicate, but do not prove, that gingival epithelium may be a source of PDGF A and B chains and that the A chain may have a more prominent role to play during early stages of healing. Expression of PDGF beta-receptor appears later at the wound site, indicating that the PDGF B isomer may regulate later wound healing events.

Adult↗
PubMed1997

Biological effects of drug-loaded biodegradable membranes for guided bone regeneration.

The biological effects of drug-loaded biodegradable novel membrane for guided bone regeneration (GBR) was evaluated. The membranes were polyglycolic acid mesh coated with poly-L-lactic acid containing flurbiprofen, tetracycline or PDGF-BB. Porous structure was generated in the membranes by using a phase inversion method. The membrane was less toxic, nicely biodegradable and biocompatible for 8 wk after implantation in the dorsal skin of the rat. The drugs released from the membranes were shown to be effective for new bone formation. Tetracycline, flurbiprofen or PDGF-BB loaded membrane was markedly effective for osteoid tissue and new bone formation in the bony defect prepared in rat calvaria to compare with that by unloaded membrane. These results suggested that drug-loaded biodegradable barrier membrane might be a potential tool for GBR in periodontal therapy.

Analysis of Variance↗
PubMed1998

Porphyromonas gingivalis lipopolysaccharide modulates the responsiveness of human periodontal ligament fibroblasts to platelet-derived growth factor.

Lipopolysaccharides (LPS) prepared from periodontopathic bacteria have been known to induce various biological responses which may lead to periodontal tissue breakdown. The purpose of this study was to determine if Porphyromonas gingivalis LPS could affect cellular functions of human periodontal ligament fibroblasts (HPLF). We showed here the responsiveness of cultured HPLF to platelet-derived growth factor (PDGF)-BB, a growth factor for mesenchymal cells, in the presence of P. gingivalis LPS. DNA synthesis of HPLF was enhanced in a dose-dependent manner when LPS were co-incubated for 48 h; thereafter, it decreased to the baseline level within 24 h incubation. The stimulating effect of PDGF-BB was further enhanced by the pretreatment of HPLF with LPS (10 micrograms/ml) for 48 h. The binding assay of [125I]PDGF-BB and the flow cytometric assay using rabbit antiserum to human PDGF receptor (PDGF-R) beta-type indicated that this enhancement was due to the increase of the number of PDGF-R beta-type on HPLF. Immunoprecipitation using antiserum to human PDGF-R beta-type also showed that the synthesis of PDGF-R beta-type was augmented in the LPS-treated HPLF. These results indicate that P. gingivalis LPS stimulate cellular proliferation and responsiveness to PDGF-BB of cultured HPLF. These cellular reactions may be mediated by PDGF-BB binding, followed by increased synthesis of the receptor protein.

Becaplermin↗
PubMed1999

Effect of recombinant human platelet-derived growth factor-BB and bone morphogenetic protein-2 application to demineralized dentin on early periodontal ligament cell response.

The purpose of this study is to investigate the early responses of human periodontal ligament cells attached to recombinant human platelet-derived growth factor-BB and bone morphogenetic protein-2 applied EDTA-demineralized dentin. One hundred and seventy-four root-planed flat dentin blocks were prepared from the mid-third of periodontally diseased human tooth roots. After demineralization with 24% EDTA (pH 7.02) 120 dentin blocks were treated with 0.5 and 1 microgram/ml rhPDGF-BB, 1 and 3 micrograms/ml rhBMP-2 and only MEM as control (24/group). Human periodontal ligament cells (HPLC) were seeded on these dentin surfaces and incubated. The alkaline phosphatase (ALP) activity and protein concentration of the attached cell were assessed at d 2, 4 and 7. Fifty-four dentin blocks were seeded with HPLC after application of 1 microgram/ml rhPDGF-BB, 3 micrograms/ml rhBMP-2 and MEM (18/group) and then incubated. At d 2, 4 and 7, the attached cells were stained and counted under light microscope. The results showed a significant increase of protein concentration and cell number in PDGF-BB treated groups than control (p < 0.05, p < 0.01) but not the ALP activity, and a significant increase of ALP activity was observed in BMP-2 treated groups than control (p < 0.05) but protein concentration and cell number remained almost the same over time. Thus, rhPDGF-BB and rhBMP-2 application to EDTA demineralized dentin surfaces promote the early human periodontal ligament cell responses by increasing cell proliferation and differentiation, respectively, which would ultimately enhance periodontal regeneration.

Adolescent↗
PubMed1997

The association of platelet-derived growth factor (PDGF) receptor tyrosine phosphorylation to mitogenic response of human osteoblastic cells in vitro.

OBJECTIVES: The purpose of this study was to make clear the relationship of human osteoblastic cell growth, induced by platelet-derived growth factor (PDGF), to PDGF receptor tyrosine phosphorylation. MATERIALS AND METHODS: Osteoblastic cells derived from human maxilla were cultured with human PDGF. The cell growth was evaluated by cell number and DNA synthesis. PDGF receptor tyrosine phosphorylation was detected by immunoblot analysis using anti-PDGF receptor alpha, beta subunits and anti-phosphotyrosine antibodies. Genistein, a tyrosine kinase inhibitor, was added to the culture to investigate the effect on osteoblastic cell growth and PDGF receptor tyrosine phosphorylation induced by PDGF. RESULTS AND CONCLUSIONS: PDGF stimulated the proliferation of human osteoblastic cells and this effect was synergetic with serum stimulation. DNA synthesis of osteoblastic cells was elevated by PDGF in a dose dependent manner at the minimum concentration of 1 ng ml-1. PDGF also induced PDGF receptor tyrosine phosphorylation within 1 min on osteoblastic cells, and tyrosine phosphorylation occurred on PDGF receptor subunits alpha and beta. Genistein inhibited cell growth and receptor tyrosine phosphorylation, which was induced by PDGF on these cells. In conclusion, human osteoblastic cell growth induced by PDGF is shown to relate to tyrosine kinase of PDGF receptors.

Becaplermin↗
PubMed2006

A time-dependent effect of PDGF-BB on adhesion and growth of cultured fibroblasts to root surfaces.

OBJECTIVE: Platelet-derived growth factor (PDGF-BB) is suggested to be a potent stimulator and a strong mitogenic agent for human periodontal ligament cells (PDL). This study aimed at assessing the effectiveness of PDGF-BB application on periodontally diseased root surfaces through attachment and growth of fibroblast cells. MATERIALS AND METHODS: Fifteen periodontally involved and five healthy teeth were selected, prepared from proximal surfaces and distributed into four groups (10 specimens per group): I: healthy; II: untreated diseased; III: scaling and root planning (SRP); and IV: SRP and PDGF-BB. Each group had three subdivisions (three specimens per group) which were incubated at three different time periods. The remaining specimen for each group was used to examine surface topography. Fibroblasts were pooled on root specimens and incubated. Results were evaluated by using scanning electron microscopy. Repeated cell counting was done within a representative standard area. RESULTS: The best results regarding PDL cell shape and density were obtained at day 3 in all experimental groups, except the diseased group. Although SRP samples showed slightly higher results in numbers of attached fibroblasts than diseased samples, they demonstrated a similar negative effect denoting incompatible root surfaces for fibroblast attachment. SRP plus PDGF-BB and healthy samples showed a comparable positive effect, suggesting a good root surface biocompatibility. Inter-group differences showed no significant differences on day 1, but statistically significant differences were found on both day 3 and day 7 incubation periods favoring groups I and IV over groups II and III. CONCLUSIONS: Platelet-derived growth factor showed a positive effect on adhesion and growth of cultured fibroblasts to periodontally diseased surfaces. Thus, PDGF-BB may have a promising role in clinical periodontics.

Adult↗
PubMed1995

Common and distinct elements in insulin and PDGF signaling.

The receptors for insulin and PDGF are tyrosine kinases that mediate distinct effects in identical cellular backgrounds. Each receptor must therefore engage a unique subset of the available signaling elements--at least partly through the selection of proteins with src-homology 2 domains (SH2 proteins). Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. Association with IRS-1 activated PtdIns 3'-kinase more effectively than association with the PDGFr. Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). Furthermore, IRS-1 binds a different subset of SH2 domain-containing proteins than does the PDGFr and regulates at least one common element (PtdIns 3'-kinase) differently than the PDGFr. These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules.

3T3 Cells↗
PubMed1995

Platelet-derived growth factor. Distinct signal transduction pathways associated with migration versus proliferation.

Figure 2 summarizes our current interpretation of data concerning signals from the activated PDGF receptor involved in directed migration and proliferation of human arterial SMC. Binding of PDGF (PDGF-BB or PDGF-AA) causes PDGF-receptor dimerization, tyrosine autophosphorylation, and subsequent binding of several molecules containing SH2 domains to the activated receptor. Binding and activation of PLC gamma by the PDGF receptor leads to PIP2 hydrolysis, resulting in generation of diacylglycerol (DAG) and IP3. Subsequently, intracellular levels of calcium are elevated as a result of IP3-mediated calcium release from intracellular compartments. The decreased levels of PIP2 and increased levels of calcium both favor actin-filament disassembly by inducing capping of actin-filament barbed ends and actin-monomer sequestration. A localized, and transient, actin-filament disassembly enables the cell to extend filopodia towards PDGF, thereby enabling chemotaxis to take place. At a later time and/or in a different compartment, actin-filament assembly is promoted by PDGF by a mechanism that is not completely understood, but that may involve small GTP-binding proteins, such as Rho, and formation of DAG. Migration on collagen requires functional alpha 2 beta 1 integrins, which may either constitute a permissive state required for a cell to migrate, or which may be actively involved in intracellular signals leading to migration. PDGF-induced DNA synthesis and proliferation involves activation of Ras, MAP kinase kinase, and MAP kinase. Cross-talk between PKA signaling and tyrosine-kinase receptor signaling results in PKA inhibition of the MAP kinase cascade, probably at the level of Raf. Activation of PI 3-kinase, or a PI 3-kinase-like enzyme, is also likely to contribute to the mitogenic effects of PDGF in these cells (Bornfeldt, unpublished observation). What determines if a SMC will migrate and/or proliferate in response to PDGF? Results are starting to emerge that show regulation of expression of molecules involved in intracellular signaling with different phenotypic states of SMC. For example, expression of PLC gamma is very low in intact vascular wall (where SMC show a "contractile phenotype"), and induced when SMC are converted to a "synthetic phenotype" in culture. Proliferation and expression of MAP kinase, but not calcium signaling, appear to be regulated by the extracellular matrix, and the profile of integrin expression is different in SMC in culture compared to SMC in the vascular wall. Thus, the relation between expression of signaling molecules involved in migration and signaling molecules involved in proliferation, as well as cross-talk between different signal-transduction pathways, may determine the net effect of PDGF.

Animals↗
PubMed1996

A novel physiological function for platelet-derived growth factor-BB in rat dermis.

1. The present experiments describe a role for platelet-derived growth factor-BB and cellular adhesion receptors towards extracellular matrix molecules (beta 1-integrins) in control of interstitial fluid pressure (Pif). 2. Pif was measured in rat skin with sharpened glass capillaries (3-7 microns) connected to a servocontrolled counter-pressure system. 3. The collagen and laminin-binding alpha 2 beta 1-integrin is involved in the control of Pif since subdermal injection (5 microliters) of monoclonal hamster anti-rat alpha 2 beta 1-integrin IgG (anti-alpha 2 beta 1) resulted in increased negativity of Pif. Control Pif averaged -0.88 +/- 0.23 mmHg (+/- S.D.) and decreased to -2.50 +/- 0.35 mmHg (P < 0.05) and -3.88 +/- 1.45 mmHg (P < 0.05) at anti-alpha 2 beta 1 concentrations of 0.56 and 1.12 mg ml-1, respectively. 4. The effect of anti-alpha 2 beta 1 was abolished when platelet-derived growth factor-BB (PDGF-BB) (200 ng ml-1) was injected together with anti-alpha 2 beta 1. 5. The time- and dose-responses of PDGF-BB to counteract increased negativity of Pif were studied further using dextran anaphylaxis as an experimental model inducing increased negativity of Pif in skin. Control Pif averaged -0.33 +/- 0.43 mmHg and fell to -4.10 +/- 1.47 mmHg within 10 min after dextran (P < 0.01). Subsequent subdermal injection of PDGF-BB at 200 ng ml-1 normalized Pif in 10-20 min which became -1.37 +/- 1.23 mmHg (P < 0.01 versus dextran, P > 0.05 versus control). PDGF-BB had little or no effect at 50 ng ml-1. PDGF-AA and basic fibroblast growth factor had no effect on Pif. 6. The in vivo function reported for PDGF-BB has not been described previously and provides further evidence for active participation of connective tissue cells in control of Pif by altering tension on extracellular matrix structures.

Animals↗
PubMed2004

A c-Jun NH2-terminal kinase inhibitor SP600125 (anthra[1,9-cd]pyrazole-6 (2H)-one) blocks activation of pancreatic stellate cells.

In response to pancreatic injury and in cell culture, pancreatic stellate cells (PSCs) are transformed ("activated") into highly proliferative myofibroblast-like cells that express alpha-smooth muscle actin and produce extracellular matrix components. Activated PSCs are implicated in the pathogenesis of pancreatic fibrosis and inflammation. We here evaluated the effects of SP600125 (anthra[1,9-cd]pyrazole-6 (2H)-one), an inhibitor of c-Jun NH(2)-terminal kinase (JNK), on the activation of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. Activation of JNK was determined by Western blotting using anti-phosphospecific JNK and c-Jun antibodies. Activation of transcription factors was determined by electrophoretic mobility shift assay. The effects of SP600125 on the key parameters of activation (chemokine production, collagen production, and proliferation) were examined. The effect of SP600125 on the activation of freshly isolated PSCs in culture also was examined. Interleukin-1beta activated both 46- and 54-kDa JNK, whereas platelet-derived growth factor-BB activated only 46-kDa JNK. SP600125 inhibited interleukin-1beta-induced JNK activity and activator protein-1 activation, but it did not affect the activation of extracellular-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-kappaB. SP600125 inhibited platelet-derived growth factor-induced proliferation, inducible monocyte chemoattractant protein-1 production, and serum-induced type I collagen production. Although SP600125 did not inhibit the transformation, it attenuated the proliferation of freshly isolated PSCs in culture. Collectively, our results suggest a role of JNK in the activation of PSCs, and a potential application of JNK inhibitors for the treatment of pancreatic fibrosis and inflammation.

Animals↗