SMART MODE:

NORMAL GENOMIC

• Bell SL, Xu G, Forstner JF
• Role of the cystine-knot motif at the C-terminus of rat mucin protein Muc2 in dimer formation and secretion.
• Biochem J. 2001; 357: 203-9
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• DNA constructs based on the 534-amino-acid C-terminus of rat mucin protein Muc2 (RMC), were transfected into COS cells and the resultant (35)S-labelled dimers and monomers were detected by SDS/PAGE of immunoprecipitates. The cystine-knot construct, encoding the C-terminal 115 amino acids, appeared in cell lysates as a 45 kDa dimer, but was not secreted. A construct, devoid of the cystine knot, failed to form dimers. Site-specific mutagenesis within the cystine knot was performed on a conserved unpaired cysteine (designated Cys-X), which has been implicated in some cystine-knot-containing growth factors as being important for intermolecular disulphide-bond formation. Dimerization of RMC was effectively abolished. Each cysteine (Cys-1-Cys-6) comprising the three intramolecular disulphide bonds of the cystine knot was then mutated. Dimer formation was impaired in each case, although much less so for the Cys-3 mutant than the others. Abnormal high-molecular-mass, disulphide-dependent aggregates formed with mutations Cys-1, Cys-2, Cys-4 and Cys-5(,) and were poorly secreted. It is concluded that the intact cystine-knot domain is essential for dimerization of the C-terminal domain of rat Muc2, and that residue Cys-X in the knot plays a key role. The structural integrity of the cystine knot, maintained by intramolecular bonds Cys-1-Cys-4, Cys-2-Cys-5 and Cys-3-Cys-6, also appears to be important for dimerization, probably by allowing correct positioning of the unpaired Cys-X residue for stable intermolecular cystine-bond formation.

• Vitt UA, Hsu SY, Hsueh AJ
• Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules.
• Mol Endocrinol. 2001; 15: 681-94
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• The cystine knot three-dimensional structure is found in many extracellular molecules and is conserved among divergent species. The identification of proteins with a cystine knot structure is difficult by commonly used pairwise alignments because the sequence homology among these proteins is low. Taking advantage of complete genome sequences in diverse organisms, we used a complementary approach of pattern searches and pairwise alignments to screen the predicted protein sequences of five model species (human, fly, worm, slime mold, and yeast) and retrieved proteins with low sequence homology but containing a typical cystine knot signature. Sequence comparison between proteins known to have a cystine knot three-dimensional structure (transforming growth factor-beta, glycoprotein hormone, and platelet-derived growth factor subfamily members) identified new crucial amino acid residues (two hydrophilic amino acid residues flanking cysteine 5 of the cystine knot). In addition to the well known members of the cystine knot superfamily, novel subfamilies of proteins (mucins, norrie disease protein, von Willebrand factor, bone morphogenetic protein antagonists, and slit-like proteins) were identified as putative cystine knot-containing proteins. Phylogenetic analysis revealed the ancient evolution of these proteins and the relationship between hormones [e.g. transforming growth factor-beta (TGFbeta)] and extracellular matrix proteins (e.g. mucins). They are absent in the unicellular yeast genome but present in nematode, fly, and higher species, indicating that the cystine knot structure evolved in extracellular signaling molecules of multicellular organisms. All data retrieved by this study can be viewed at http://hormone.stanford.edu/.

• Patruno M, Thorndyke MC, Candia Carnevali MD, Bonasoro F, Beesley PW
• Growth factors, heat-shock proteins and regeneration in echinoderms.
• J Exp Biol. 2001; 204: 843-8
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• The study of regeneration in armed echinoderm species, including crinoids, ophiuroids and asteroids, is attracting increasing attention. Recent interest has focused on the presence and potential role of growth factors, including members of the nerve growth factor (NGF) and transforming growth factor-beta (TGF-beta) families, in the regenerative process and their possible relationship to the normal developmental (ontogenetic) regulatory cascade. In addition, the expression patterns of the heat-shock family of stress proteins (Hsps) during regeneration are also important. Their role forms part of a normal stress response to the trauma of autotomy in combination with a putative function in tissue remodelling and associated protein turnover during regeneration. The temporal dynamics of the stress response may also be strongly indicative of environmentally adaptive pressures operating on these systems.

• Faiz Kabir Uddin Ahmed A et al.
• In situ expression of fibrogenic growth factors and their receptors in biliary atresia: comparison between early and late stages.
• J Pathol. 2000; 192: 73-80
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• Progressive fibrosis, despite successful surgical treatment, is one of the serious complications of biliary atresia. To understand the mechanism of this fibrosis, the in situ expression of fibrogenic growth factors (TGF-beta and PDGF) and their corresponding receptors was studied by immunohistochemistry using frozen sections. The results were compared between the early (n=12) and late (n=6) stages. The early stage was characterized by abundant expression of all ligands and receptors, together with type I procollagen (PC-I). The major cellular sources were activated fibroblasts/myofibroblasts distributed mostly in the portal tracts. Macrophages also expressed all the ligands and the receptors, but to a lesser degree. Bile duct cells strongly expressed TGF-beta RI and RII and PDGF AA and BB, but focally expressed TGF-beta. All of these decreased in the late stage of biliary atresia. These results suggest that TGF-beta and PDGF play important roles in the fibrogenesis of biliary atresia, especially in its early stage, acting either by autocrine or paracrine mechanisms involving activated fibroblasts/myofibroblasts, bile duct cells, and macrophages.

• Kadono T, Kikuchi K, Nakagawa H, Tamaki K
• Expressions of various growth factors and their receptors in tissues from neurofibroma.
• Dermatology. 2000; 201: 10-4
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• BACKGROUND: Platelet-derived growth factor BB (PDGF-BB) and transforming growth factor beta are known to enhance the growth of neurofibroma-derived cells from neurofibromatosis type 1 (NF-1) patients. OBJECTIVE: This study aims to elucidate whether these growth factors and their receptors are up-regulated in NF-1 patients. METHODS: Tissues and culture cells from neurofibroma in NF-1 patients, nontumor lesions in NF-1 patients, and the skin of normal controls were collected. To evaluate the expressions of growth factors and their receptors, reverse-transcriptase polymerase chain reaction and immunohistochemistry were performed. RESULTS: PDGF-beta receptor subunit was expressed in the neurofibroma tissues from NF-1 patients, but not in the nontumorous tissues from NF-1 patients or skin from normal controls. As for the other factors, there were no significant differences among these tissues. Neurofibroma sections also stained positive for the PDGF-beta receptor subunit. CONCLUSIONS: The interaction of PDGF and PDGF-beta receptor subunit may be important in the tumorigenesis of NF-1.

• Kletsas D et al.
• Fibroblast responses to exogenous and autocrine growth factors relevant to tissue repair. The effect of aging.
• Ann N Y Acad Sci. 2000; 908: 155-66
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• The aging process is often associated with impaired wound healing, but the cellular and molecular mechanisms implicated are not completely understood. Accordingly, we have investigated the response of human fibroblasts from donors of various ages to platelet-derived and autocrine growth factors, in terms of mitogenicity as well as extracellular matrix synthesis and degradation. Our data indicate that fibroblast responses persist during aging, suggesting the involvement of systemic factors in the regulation of the healing process. In this context, we have found that neutral endopeptidase-24.11, a metalloproteinase controlling the action of neuroendocrine peptides and also of immunocyte chemotaxis, is overexpressed during aging. Finally, the connection between these data and those from in vitro aging studies is discussed.

• Rosenkranz S, Bohm M, Kazlauskas A
• [Pathophysiologic significance of growth factors and new therapeutic concepts in cardiovascular disease]
• Med Klin. 1999; 94: 496-504
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• Peptide growth factors such as PDGF, FGF, VEGF, and TGF-beta play a critical role in the pathogenesis of cardiovascular diseases. In addition to their pathophysiological role in atherosclerosis and myocardial remodeling, growth factors also promote beneficial effects such as stimulation of angiogenesis and formation of collateral vessels in ischemic tissue. This review focuses on the mechanisms of action and signal relay cascades of peptide growth factors, and summarizes novel therapeutic approaches in cardiovascular medicine. These approaches include both inhibition of growth factors in order to suppress pathogenic processes, and stimulation of growth factors to promote their beneficial effects.

• Krieglstein K
• [Synergistic effect of cytokines let neurotrophic functions begin]
• Anat Anz. 1999; 181: 423-5

• Limat A, French LE
• Therapy with growth factors.
• Curr Probl Dermatol. 1999; 27: 49-56

• Garg AK
• The future role of growth factors in bone grafting.
• Dent Implantol Update. 1999; 10: 5-7

• Weisenhorn DM, Roback J, Young AN, Wainer BH
• Cellular aspects of trophic actions in the nervous system.
• Int Rev Cytol. 1999; 189: 177-265
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• During the past three decades the number of molecules exhibiting trophic actions in the brain has increased drastically. These molecules promote and/or control proliferation, differentiation, migration, and survival (sometimes even the death) of their target cells. In this review a comprehensive overview of small diffusible factors showing trophic actions in the central nervous system (CNS) is given. The factors discussed are neurotrophins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, insulin-like growth factors, ciliary neurotrophic factor and related molecules, glial-derived growth factor and related molecules, transforming growth factor-beta and related molecules, neurotransmitters, and hormones. All factors are discussed with respect to their trophic actions, their expression patterns in the brain, and molecular aspects of their receptors and intracellular signaling pathways. It becomes evident that there does not exist "the" trophic factor in the CNS but rather a multitude of them interacting with each other in a complicated network of trophic actions forming and maintaining the adult nervous system.

• Moulin V, Lawny F, Barritault D, Caruelle JP
• Platelet releasate treatment improves skin healing in diabetic rats through endogenous growth factor secretion.
• Cell Mol Biol (Noisy-le-grand). 1998; 44: 961-71
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• Although impaired skin wound healing in diabetes is a well established phenomenon, virtually nothing is known of its underlying mechanism. We have demonstrated that diabetic skin exhibited a significant deficiency in total mitogenic activity, notably a diminution in FGF1, FGF2 and TGFbeta-like molecules. We postulated that impaired skin healing could be explained by a decreased expression of endogenous growth factors that could be compensated by a platelet releasate (PR) added in situ. Histological studies showed that PR treatment improved tissue repair and restored disturbed healing steps observed in untreated diabetic rat skin although reepithelialization was not altered. Our data demonstrate that PR treatment induces important modulations of the quantity and the kinetic of secretion of endogenous growth factors in the wounds. Although exogenous factors present in PR could no longer be quantified in the wounds after 3 days, our results indicated that factors contained in PR may have: 1) a direct and immediate effect on the growth of neodermal cells, combined to 2) a long term stimulation of endogenous growth factor synthesis in situ during cutaneous wound healing in diabetic rats.

• Jensen RL
• Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review.
• Surg Neurol. 1998; 49: 189-95
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• BACKGROUND: We review the role of peptide growth factors in angiogenesis and progression of low grade glial tumors to higher grade glioblastoma multiforme (GBM). METHODS: Vascular pathology is a key feature of glioblastoma multiforme characterized by hypervascularity, vascular permeability, and hypercoagulability. RESULTS: Vascular endothelial growth factor (VEGF) can mediate all of these effects, but by itself does not promote malignant growth. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor beta (TGF-beta) are implicated in the angiogenesis of a number of tumors including those of glial origin. CONCLUSIONS: These growth factors are suggested to play a role in autocrine and/or paracrine mediated tumorogenesis of astrocytic tumors. VEGF secretion might be the product of induction by physiologic concentrations of other growth factors with VEGF being the common pathway of neovascularization and progression to GBM.

• Feige JJ, Vilgrain I, Brand C, Bailly S, Souchelnitskiy S
• Fine tuning of adrenocortical functions by locally produced growth factors.
• J Endocrinol. 1998; 158: 7-19

• Nagtegaal ID, Lakke EA, Marani E
• Trophic and tropic factors in the development of the central nervous system.
• Arch Physiol Biochem. 1998; 106: 161-202

• Okuno M, Moriwaki H
• [Liver fibrogenesis and cytokines]
• Nippon Shokakibyo Gakkai Zasshi. 1998; 95: 743-9

• Graham A
• The use of growth factors in clinical practice.
• J Wound Care. 1998; 7: 536-40

• Marx RE, Carlson ER, Eichstaedt RM, Schimmele SR, Strauss JE, Georgeff KR
• Platelet-rich plasma: Growth factor enhancement for bone grafts.
• Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998; 85: 638-46
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• Platelet-rich plasma is an autologous source of platelet-derived growth factor and transforming growth factor beta that is obtained by sequestering and concentrating platelets by gradient density centrifugation. This technique produced a concentration of human platelets of 338% and identified platelet-derived growth factor and transforming growth factor beta within them. Monoclonal antibody assessment of cancellous cellular marrow grafts demonstrated cells that were capable of responding to the growth factors by bearing cell membrane receptors. The additional amounts of these growth factors obtained by adding platelet-rich plasma to grafts evidenced a radiographic maturation rate 1.62 to 2.16 times that of grafts without platelet-rich plasma. As assessed by histomorphometry, there was also a greater bone density in grafts in which platelet-rich plasma was added (74.0% +/- 11%) than in grafts in which platelet-rich plasma was not added (55.1% +/- 8%; p = 0.005).

• Flyvbjerg A et al.
• Diabetic kidney disease: the role of growth factors.
• Nephrol Dial Transplant. 1998; 13: 1104-7

• Kletsas D, Sassi D, Franchini A, Ottaviani E
• PDGF and TGF-beta induce cell shape changes in invertebrate immunocytes via specific cell surface receptors.
• Eur J Cell Biol. 1998; 75: 362-6
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• The presence of PDGF receptor-alpha- and -beta- and TGF-beta-receptor (type II)-like molecules on the plasma membranes of the immunocytes of the mollusc Mytilus galloprovincialis was demonstrated by an immunocytochemical procedure. Furthermore, the present study provides evidence that PDGF-AB and TGF-beta1 provoke cell shape changes in immunocytes via interactions with the respective receptors and that these extracellular signals are transduced along the phosphoinositide signaling pathway.

• Kletsas D, Basdra EK, Papavassiliou AG
• Mechanical stress induces DNA synthesis in PDL fibroblasts by a mechanism unrelated to autocrine growth factor action.
• FEBS Lett. 1998; 430: 358-62
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• Periodontal regeneration is thought to require the proliferation of stress-sensitive periodontal ligament (PDL) fibroblast cells. The influence of physiological amounts of mechanical stretching on the DNA synthesis potential of human PDL fibroblasts was examined by means of an established, simple in vitro system of stretch application. A significant increase in the relative levels of incorporation of tritiated thymidine was observed in cultures stretched for 1-6 h. Neutralising antibodies for platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) did not blunt the DNA synthesis induction. This mitogenic response to stretch appears to be independent of an autocrine mechanism involving growth factors in general, because stretch-conditioned medium, when transferred to non-stretched fibroblasts, did not mimic the mitogenic effect of stretch.

• Anderson TJ, Lapp CA, Billman MA, Schuster GS
• Effects of transforming growth factor-beta and platelet-derived growth factor on human gingival fibroblasts grown in serum-containing and serum-free medium.
• J Clin Periodontol. 1998; 25: 48-55
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• Both transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) have been shown to affect cell proliferation in vitro. The hypothesis being tested was that the effects of the 2 cytokines would be modulated by the presence of serum in the medium. Gingival fibroblasts, obtained from periodontally healthy patients, were maintained in primary culture. Dose response experiments were performed for each growth factor in serum-free medium and in medium containing natural or heat-inactivated fetal bovine serum (10% FBS). Changes in cell numbers were quantified by crystal violet staining. The optimal concentrations of the individual factors (10 ng/ml TGF-beta1, 20 ng/ ml PDGF-BB) were then used when the 2 factors were tested in various sequences. In serum-free medium or in medium with 10% natural serum, the response to PDGF-BB was dose-dependent up to 40 ng/ml; however, with 10% heat-inactivated serum, the maximal response was seen at 20 ng/ml. The largest increase in cell numbers was produced by the simultaneous exposure to the two cytokines, rather than a sequential presentation. The findings suggest that the 48-h growth response of human gingival fibroblasts to 10 ng/ml TGF-beta1 or 20 ng/ ml PDGF-BB in serum-free medium was equivalent to growth obtained in medium containing heat-inactivated 10% FBS without added growth factors.

• Ballock RT, Heydemann A, Izumi T, Reddi AH
• Regulation of the expression of the type-II collagen gene in periosteum-derived cells by three members of the transforming growth factor-beta superfamily.
• J Orthop Res. 1997; 15: 463-7
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• Although transforming growth factors-beta and bone morphogenetic proteins are both capable of inducing bone formation in vivo, the target cells of their osteoinductive actions may be different. To evaluate periosteal cells as potential targets of the actions of transforming growth factor-beta and bone morphogenetic protein, we investigated the ability of three members of the transforming growth factor-beta superfamily to modulate expression of the gene encoding the alpha 1(II) chain of type-II collagen in periosteum-derived cells in vitro. The results demonstrate that transforming growth factor-beta mRNA is expressed by periosteum-derived cells and that exogenous transforming growth factor-beta 1 acts to upregulate expression of the gene encoding collagen alpha 1(II). This effect was observed as early as 12 hours after administration of transforming growth factor-beta 1 but was not observed in response to bone morphogenetic proteins 3 or 4. No synergy was demonstrated between transforming growth factor-beta 1 and bone morphogenetic protein-3 in the ability to upregulate expression of the collagen alpha 1(II) gene. These results support the hypothesis that committed periosteal mesenchymal cells are cellular targets of the action of transforming growth factor-beta.

• Creedon DJ, Tuttle JB
• Synergistic increase in nerve growth factor secretion by cultured vascular smooth muscle cells treated with injury-related growth factors.
• J Neurosci Res. 1997; 47: 277-86
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• Vascular smooth muscle (VSM) cells comprise one of the primary targets of the sympathetic nervous system and have been shown to secrete nerve growth factor (NGF). There is increasing evidence that changes in the levels of NGF in the adult may underlie certain pathological conditions. To investigate the potential role of altered NGF production in vascular disease, VSM cell cultures were treated with injury-related growth factors and the culture medium was assayed for NGF using a two-site enzyme-linked immunosorbent assay (ELISA). Platelet-derived growth factor (PDGF), a potent VSM mitogen, caused a dose-dependent increase in NGF secretion. After 4 hr, PDGF-treated cultures contained 10 times more NGF than control cultures. NGF release remained elevated for 48 hr, but the peak secretion occurred in the first 12 hr after treatment. Transforming growth factor beta (TGF-beta) caused a fivefold increase in NGF at 4 hr when added alone, but synergized with PDGF yielding approximately 50 times more NGF than control cultures. TGF-beta and epidermal growth factor (EGF) also displayed synergism. In contrast, basic fibroblast growth factor (bFGF), which had a modest effect alone, appeared to be additive with TGF-beta. Similarly, interleukin 1-beta (IL-1 beta), which mediates increased NGF synthesis in sciatic nerve lesions (Lindholm et al.: Nature 330:658-659, 1987), showed no synergism with TGF-beta.

• Haralson MA
• Transforming growth factor-beta, other growth factors, and the extracellular matrix.
• J Lab Clin Med. 1997; 130: 455-8

• Einhorn TA, Trippel SB
• Growth factor treatment of fractures.
• Instr Course Lect. 1997; 46: 483-6

• Schuman E
• Growth factors sculpt the synapse.
• Science. 1997; 275: 1277-8

• Sato A et al.
• Cystine knot of the gonadotropin alpha subunit is critical for intracellular behavior but not for in vitro biological activity.
• J Biol Chem. 1997; 272: 18098-103
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• The common alpha subunit of glycoprotein hormones contains five disulfide bonds. Based on the published crystal structure, the assignments are 7-31, 59-87, 10-60, 28-82, and 32-84; the last three comprise the cystine knot, a structure also seen in a variety of growth factors. Previously, we demonstrated that the efficiency of secretion and the ability to form heterodimers by alpha subunits bearing single cysteine residue mutants in the cystine knot were significantly reduced. These results suggested that the cystine knot is critical for the intracellular integrity of the subunit. To assess if the presence of the free thiol affected the secretion kinetics, we constructed paired cysteine mutants of each disulfide bond of the alpha subunit. The secretion rate for these monomers was comparable with wild type except for the alpha-10-60 mutant, which was 40% lower. The recovery of the alpha7-31 and alpha59-87 mutants was greater than 95%, whereas for the cystine knot mutants, it was 20-40%. Co-expression of the wild-type chorionic gonadotropin beta subunit with double cysteine mutants did not enhance the recovery of alpha mutants in the media. Moreover, compared with wild-type, the efficiency of heterodimer formation of the alpha10-60 or alpha32-84 mutants was less than 5%. Because subunit assembly is required for biological activity, studies on the role of these disulfide bonds in signal transduction were not possible. To bypass the assembly step, we exploited the single chain model, where the alpha and beta subunits are genetically fused. The recovery of secreted tethered gonadotropins bearing mutations in the cystine knot was increased significantly. Although dimer-specific monoclonal antibodies discriminated the conformation of single chain alpha10-60 and alpha32-84 mutants from the native heterodimer, these mutants were nevertheless biologically active. Thus, individual bonds of cystine knot are important for secretion and heterodimer formation but not for in vitro bioactivity. Moreover, the data suggest that the native heterodimer configuration is not a prerequisite for receptor binding or signal transduction.

• Vignola AM et al.
• Growth factors in asthma.
• Monaldi Arch Chest Dis. 1997; 52: 159-69
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• Asthma is a chronic inflammatory disease of the airways, with associated repair processes. Both inflammatory and repair processes appear to be strictly related, and can lead to several histopathological alterations of the bronchial mucosa, such as the shedding of epithelium and increased thickness of the basement membrane. The integrity as well as the alterations of the bronchial structure are the consequence of several biological events, such as cell proliferation and death, cell activation and inhibition, and extracellular matrix (ECM) production and degradation. These events are critically regulated by polypeptides called growth factors (GFs), which are able, functioning in an autocrine and paracrine fashion, to affect and modulate cell functions and ECM turnover. Although the importance of GFs has been widely demonstrated in other pulmonary conditions, such as lung fibrotic diseases, their possible involvement in the pathogenesis of inflammatory and postinflammatory processes in asthma is still not completely clear. The aim of the present review was to discuss the biological evidence concerning the role of several growth factors, such as transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), granulocyte/macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF) and endothelin, in asthma and chronic bronchitis.

• Yellon RF, Szeremeta W, Grandis JR, Diguisseppe P, Dickman PS
• Role of subglottic injury, gastric juice, and peptide growth factors in a porcine model.
• Int Anesthesiol Clin. 1997; 35: 115-25

• Eigenbrot C, Gerber N
• X-ray structure of glial cell-derived neurotrophic factor at 1.9 A resolution and implications for receptor binding.
• Nat Struct Biol. 1997; 4: 435-8
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• The crystal structure of glial cell-derived neurotrophic factor (GDNF) reveals two independent copies of the dimer that differ significantly through a hinge bending at the central, disulphide-rich region. GDNF is compared with other members of the TGF-beta family, and potential receptor binding surfaces are identified.

• Dzurik R, Pontuch P, Spustova V
• Modulators and mediators of kidney disease progression: new targets of prevention and treatment.
• Bratisl Lek Listy. 1997; 98: 663-6
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• BACKGROUND: Hemodynamic (i.e. hyperfiltration) and metabolic (i.e. insulin resistance) changes are the targets of the present preventive measures of kidney disease progression. New horizons of molecular nephrology have extended the possibilities in the proliferation research. OBJECTIVES: To review evidence on the significance of proliferative processes and the possibilities of interfering with proliferation. METHODS: A review of experimental and clinical studies elucidating the significance of thromboxane, platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) for the proliferation and kidney disease progression. RESULTS: Proliferation participates in the development and progression of glomerulosclerosis and interstitial fibrosis. A number of growth factors and cytokines trigger and accelerate the progression of kidney diseases. A number of PDGF antagonists (i.e. simvastatin, heparin, trapidil, tertatol and low protein diet) attenuate the kidney disease progression. CONCLUSIONS: Even the present knowledge enables to improve further the kidney disease treatment schedules. (Tab. 3, Ref. 22.)

• Nimni ME
• Polypeptide growth factors: targeted delivery systems.
• Biomaterials. 1997; 18: 1201-25
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• Growth factors are becoming extremely valuable tools in our attempts to understand the mechanisms that modulate cellular activities. Their targeting to appropriate cells and maintaining adequate pharmacological levels becomes essential, particularly in view of the different effects that these compounds have on various cells and the dose dependence of their response. Within this context, this review focuses primarily on the delivery of growth factors involved in the processes of wound healing and tissue repair.

• Mathe G
• Does (anti) growth factor intervention in the mechanism scheme of atheroma offer us a synthetic simplification or more chaotic complexity?
• Biomed Pharmacother. 1996; 50: 233-4

• Hulth A, Johnell O, Miyazono K, Lindberg L, Heinegard D, Heldin CH
• Effect of transforming growth factor-beta and platelet-derived growth factor-BB on articular cartilage in rats.
• J Orthop Res. 1996; 14: 547-53
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• The short-term and long-term effects on the growth zone in articular cartilage of transforming growth factor-beta 1 and platelet-derived growth factor-BB injected intraarticularly into the knee joint of growing rats were investigated. The changes induced by five injections of 0.5 micrograms of transforming growth factor-beta 1 included a rapid decrease in the size and number of hypertrophic cells and an enhanced subchondral bone formation. The changes were most marked in the patella but were also apparent in the tibia and femur. The proliferating cells became swollen and lost their normal organization. From the seventh day of the experiment to about 3 weeks, the matrix stained intensely with safranin O for proteoglycans. The alterations induced by transforming growth factor-beta also included synovial fibroplasia and synovitis, consisting predominantly of mononuclear cells. Localised necroses in the cartilage sometimes appeared after 21 days. In long-term studies, destroyed cartilage was found in three of six rats and partial ossification of the joint cartilage was found in two after 90 and 180 days. Ossicles developed in the tendons in all six patellae. Injection of platelet-derived growth factor-BB resulted in an early and transitory minor increase in the osteogenic activity in the zone between cartilage and red bone marrow and later produced an ossicle in one of four tendons. None of the other changes noted after injection of transforming growth factor was observed.

• Howell TH, Martuscelli G, Oringer J
• Polypeptide growth factors for periodontal regeneration.
• Curr Opin Periodontol. 1996; 3: 149-56
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• The regeneration of periodontal attachment apparatus is particularly difficult to achieve, primarily because of the presence of many different kinds of tissue that must be restored to produce a functional unit. Traditional methods aimed at regenerating the periodontium have limited indications, and their results are not predictable. Recently, investigators have begun to understand the cellular processes necessary for repair and regeneration of periodontal tissues. Proteins called growth factors have been identified that coordinate these cellular events. The growth factors that may contribute to periodontal regeneration include platelet-derived growth factor, insulin-like growth factor, transforming growth factor-beta, and bone morphogenetic proteins. In vitro studies have demonstrated the positive effects of these factors on a number of cell types essential for periodontal regeneration. For instance, it has been shown that platelet-derived and insulin-like growth factors promote proliferation of osteoblasts an periodontal ligament cell-derived fibroblasts. Animal models have also been used to verify that growth factors can enhance regeneration in vivo following periodontal disease and as an adjunct to implant placement. In the future, human clinical trials will be required to identify the ideal growth factors, their proper doses, and the most suitable carrier system for them.

• Yoshida M, Hayashi S
• [Role of TGF-beta and PDGF on the pathogenesis of pulmonary fibrosis--analysis by in vivo gene transfer]
• Nippon Rinsho. 1996; 54: 418-22
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• To elucidate the relevance of transforming growth factor (TGF)-beta 1 and platelet-derived growth factor (PDGF)-B to the pathogenesis of pulmonary fibrosis, we introduced each of these expression vectors via trachea into Wistar rat to overexpress them locally in the lungs by hemagglutinating virus of Japan (HVJ)-liposome method. The TGF-beta 1 gene induced significant proliferatin of fibroblasts and deposition of collagen fibrils with mild cellular infiltration. The PDGF-B gene induced mild fibrotic changes with some cellular infiltration. These findings suggest that both factors may be very closely relevant to the pathogenesis of lung fibrosis.

• Spustova V, Oksa A, Dzurik R
• [The role of platelet-derived growth factor in progression of nephropathy]
• Vnitr Lek. 1996; 42: 842-8
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• The platelet growth factor (PDGF) is a potent proliferative factor which stimulates the proliferation of the kidneys in particular of mesangial cells and moreover by stimulating the production of the transforming growth factor beta (TGF-beta) it stimulates also proliferation of the mesangium, glomerulosclerosis and obviously also interstitial fibrosis. By these mechanisms it participates in the progression of experimental and human nephropathies. Production of PDGF can be suppressed by a low protein diet, heparin, acetylsalicylic acid, dipyridamol, and some new antagonists are being developed. These findings were assembled in experimental investigations and must be confirmed in clinical trials.

• Lind M
• Growth factors: possible new clinical tools. A review.
• Acta Orthop Scand. 1996; 67: 407-17
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• Bone tissue contains numerous cell-to-cell signaling peptides called growth factors with potent effects on bone cell metabolism. In vivo studies over the last 5 years have demonstrated that growth factors can stimulate bone formation and bone healing and these results have made them candidates for use in orthopedic surgery. In numerous clinical conditions enhanced bone formation and bone healing could improve the results of surgery; clinical trials using growth factors to stimulate bone formation in spinal surgery, and to stimulate healing of bone defects, have been initiated. Growth factors for clinical use will become commercially available in the near future. This review describes the main growth factors and their actions in vitro and in vivo in relation to bone tissue and bone healing. Possible areas for clinical use are also discussed.

• Paul LC, Saito K, Davidoff A, Benediktsson H
• Growth factor transcripts in rat renal transplants.
• Am J Kidney Dis. 1996; 28: 441-50
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• Locally produced cytokines and growth factors may mediate tissue remodelling processes, as observed in renal transplants exposed to ischemia or acute rejection episodes. The present study was designed to investigate mRNA transcript levels of platelet-derived growth factor (PDGF)-receptor beta, PDGF-A, PDGF-B, fibroblast growth factor-1, and transforming growth factor beta 1 in normal rat kidneys, in kidneys following contralateral nephrectomy and in renal transplants with acute or chronic rejection. Platelet-derived growth factor-receptor beta mRNA levels increased significantly in syngeneic and allogeneic transplants in the first week after transplantation and in allogeneic transplants with chronic rejection. Immunohistochemistry showed induction of PDGF-receptor beta protein expression on vascular wall cells in such grafts. Platelet-derived growth factor-A chain mRNA levels increased in day 3 allografts and in syngeneic LEW grafts, while PDGF-B chain mRNA levels showed no significant changes with transplantation. Fibroblast growth factor-1 mRNA levels were detectable in normal kidneys, tended to decrease with acute rejection, and increased significantly in chronic rejection. Transforming growth factor-beta 1 transcripts increased in acute and chronic rejection; immunohistochemistry showed predominantly glomerular localization of the transforming growth factor-beta 1 protein. We conclude that transplantation and rejection are associated with changes in the intragraft mRNA levels for several growth factors; chronic rejection is characterized by an increase in fibroblast growth factor-1 and transforming growth factor-beta 1 transcript levels.

• Nikolics K, Hefti F, Thomas GR, Gluckman PD
• Trophic factors and their role in the postischemic brain.
• Adv Neurol. 1996; 71: 389-402

• Griffith DL, Keck PC, Sampath TK, Rueger DC, Carlson WD
• Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor beta superfamily.
• Proc Natl Acad Sci U S A. 1996; 93: 878-83
• Display abstract

• We report the three-dimensional structure of osteogenic protein 1 (OP-1, also known as bone morphogenetic protein 7) to 2.8-A resolution. OP-1 is a member of the transforming growth factor beta (TGF-beta) superfamily of proteins and is able to induce new bone formation in vivo. Members of this superfamily share sequence similarity in their C-terminal regions and are implicated in embryonic development and adult tissue repair. Our crystal structure makes possible the structural comparison between two members of the TGF-beta superfamily. We find that although there is limited sequence identity between OP-1 and TGF-beta 2, they share a common polypeptide fold. These results establish a basis for proposing the OP-1/TGF-beta 2 fold as the primary structural motif for the TGF-beta superfamily as a whole. Detailed comparison of the OP-1 and TGF-beta 2 structures has revealed striking differences that provide insights into how these growth factors interact with their receptors.

• Gombotz WR, Pankey SC, Bouchard LS, Phan DH, MacKenzie AP
• Stability, characterization, formulation, and delivery system development for transforming growth factor-beta 1.
• Pharm Biotechnol. 1996; 9: 219-45

• Hoyle GW, Brody AR
• Gene expression in rodent model of environmental lung disease.
• Ann N Y Acad Sci. 1996; 796: 162-72

• Unsicker K
• GDNF: a cytokine at the interface of TGF-betas and neurotrophins.
• Cell Tissue Res. 1996; 286: 175-8

• El Nahas AM
• Glomerulosclerosis: intrinsic and extrinsic pathways.
• Nephrol Dial Transplant. 1996; 11: 773-7

• Tajima S, Izumi T
• Differential in vitro responses of elastin expression to basic fibroblast growth factor and transforming growth factor beta 1 in upper, middle and lower dermal fibroblasts.
• Arch Dermatol Res. 1996; 288: 753-6
• Display abstract

• Elastin mRNA levels were measured in cultured skin fibroblasts derived from upper, middle and lower dermal layers. The elastin mRNA levels were highest in the fibroblasts from the upper dermal layer and lowest in the lower dermal fibroblasts. Modulation of elastin expression by basic fibroblast growth factor and transforming growth factor beta 1 in the dermal fibroblasts was also studied. Basic fibroblasts growth factor downregulated elasin expression in the upper dermal fibroblasts but did not significantly change elastin expression in the middle and lower dermal fibroblasts. Upregulation of elastin expression by transforming growth factor beta 1 was greater in the upper dermal fibroblasts than in the middle and lower dermal fibroblasts. Platelet-derived growth factor induced no significant changes in the three types of dermal fibroblasts. The results suggest that the differential responses of elastin expression to potent modulators may be at least partially responsible for the abnormal elastin metabolism specifically observed in the upper dermal layer.

• Garcia-Bolao I, Merino J, Martinez A, Grau A, Alegria E, Martinez-Caro D
• Effect of hypercholesterolaemia on platelet growth factors.
• Eur J Clin Invest. 1996; 26: 929-35
• Display abstract

• Evidence from several sources suggests that important interactions occur between platelets and low-density lipoproteins. This study was undertaken to find out if diet-induced hypercholesterolaemia affects the growth factor content in circulating platelets. Minipigs were fed either normal diet supplemented with 2% cholesterol (n = 12) or normal diet alone (n = 12). After 4 months, mean platelet volume was significantly lower (P < 0.05) and monocyte count was significantly higher (P < 0.05) in the cholesterol group. Serum and intraplatelet levels of platelet-derived growth factor (BB homodimer) and transforming growth factor beta 1 were statistically unchanged after diet. Hypercholesterolaemia did not affect the proliferative effect of either serum or platelet lysates on porcine vascular smooth muscle cells and Swiss-3T3 cells in culture. A significant positive correlation between Swiss-3T3 and smooth muscle cell proliferation was present in both groups. These results suggest that the atherosclerosis-promoting effect of hypercholesterolaemia cannot be explained by its direct effect on smooth muscle cell proliferation or by changes in serum or intraplatelet concentrations of growth factors.

• Rodriguez A, Castano M, Pena L, Sanchez MA, Nieto A, Rodriguez M
• Immunocytochemical detection of growth factors (PDGF and TGF beta) in equine chronic pneumonia.
• Res Vet Sci. 1996; 60: 82-7
• Display abstract

• The roles played by platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta) in the development of pulmonary fibrosis in equine chronic pneumonia varied greatly. Macrophages, epithelial cells and fibroblasts were identified as a source of PDGF, the principal role of which was related to its mitotic effect on epithelial cells, and particularly on fibroblasts in the final phase of the disease. TGF beta was detected in epithelial cells in all three phases of the disease and in fibroblasts in the last phase. However, the role of TGF beta in this pulmonary disease is not clear because its expression in the cytoplasm of fibroblasts in areas of strong collagenation during the last phase was weak. Nonetheless, it was responsible for the production and release of collagen during the stage of total fibrosis.

• Chen X
• [Strengthen the study on the relation between cytokines and glomerulosclerosis]
• Zhonghua Yi Xue Za Zhi. 1996; 76: 403-4

• Mott HR, Campbell ID
• Four-helix bundle growth factors and their receptors: protein-protein interactions.
• Curr Opin Struct Biol. 1995; 5: 114-21
• Display abstract

• Many growth factors and cytokines promote receptor clustering on binding. At least three different protein-protein interaction sites are involved: cytokine-receptor I, cytokine-receptor II and receptor I-receptor II. Although structural data on these complexes are limited, recent structural and mutagenesis studies of the four-helix bundle class of cytokines are clarifying the nature of the complexes formed.

• McAnulty RJ, Laurent GJ
• Pathogenesis of lung fibrosis and potential new therapeutic strategies.
• Exp Nephrol. 1995; 3: 96-107

• Carey I, Zehner ZE
• Regulation of chicken vimentin gene expression by serum, phorbol ester, and growth factors: identification of a novel fibroblast growth factor-inducible element.
• Cell Growth Differ. 1995; 6: 899-908
• Display abstract

• Vimentin is a cytoskeletal protein that belongs to the intermediate filament protein family. It is normally expressed in cells of mesenchymal origin and is developmentally as well as cell cycle regulated. Multiple silencer elements as well as unique antisilencer element are responsible for regulating the chicken vimentin gene. The silencer elements bind a protein of M(r) 90,000 (the silencer protein), whereas the antisilencer element binds a protein of M(r) 110,000-120,000 (the antisilencer protein). In this study, we examined the effect of serum, phorbol ester, transforming growth factor beta, and fibroblast growth factor of gene expression and identify the regions in the 5'-end of the chicken vimentin gene responsible for induction. The binding activity of both the silencer and the antisilencer proteins are affected by 12-O-tetradecanoylphorbol-13-acetate treatment, whereas the antisilencer element is inducible by fibroblast growth factor.

• Noguti T et al.
• Insect prothoracicotropic hormone: a new member of the vertebrate growth factor superfamily.
• FEBS Lett. 1995; 376: 251-6
• Display abstract

• Prothoracicotropic hormone (PTTH) is a brain neurosecretory protein that controls insect development. PTTH of the silkmoth Bombyx mori is a homodimeric protein, the subunit of which consists of 109 amino acids. Clear-cut sequence similarity to any other proteins has not been observed. By disulfide-bond pattern analysis and modeling of the PTTH structure based on the known three-dimensional (3D) structures of growth factor family with cystine-knot motif, we propose that the PTTH protomer adopts the fold unique to the structural superfamily of the growth factors, beta-nerve growth factor (beta-NGF), transforming growth factor-beta 2 (TGF-beta 2), and platelet-derived growth factor-BB (PDGF-BB). The insect neurohormone PTTH appears to be a member of the growth factor superfamily, sharing a common ancestral gene with the three vertebrate growth factors, beta-NGF, TGF-beta 2 and PDGF-BB.

• Zagzag D
• Angiogenic growth factors in neural embryogenesis and neoplasia.
• Am J Pathol. 1995; 146: 293-309
• Display abstract

• "Blood vessels have the power to increase within themselves which is according to the necessity whether natural or diseased. As a further proof that this is a general principle, we find that all growing parts are much more vascular than those that are come to their full growth; because growth is an operation beyond the simple support of the part. This is the reason why young animals are more vascular than those that are full grown. This is not peculiar to the natural operation of growth, but applies also to disease and restoration."

• Lind M, Deleuran B, Thestrup-Pedersen K, Soballe K, Eriksen EF, Bunger C
• Chemotaxis of human osteoblasts. Effects of osteotropic growth factors.
• APMIS. 1995; 103: 140-6
• Display abstract

• The in vitro chemotactic response of human osteoblasts was investigated towards the following growth factors: TGF-beta, PDGFs, FGFs and IGFs. Human osteoblasts grown from trabecular bone after enzymatic digestion were studied. TGF-beta stimulated the migration of human osteoblasts in a dose-dependent manner with a four-fold increase in migrated cells at 100 pg/ml, which was the optimum concentration. PDGF-BB also stimulated migration four-fold in a dose-dependent manner with a maximum response at 10 ng/ml. PDGF-AA, IGF-I and IGF-II stimulated migration two-fold at 100 ng/ml. The results show that TGF-beta and PDGF-BB are important regulators of human osteoblast migration, but other growth factors IGF-I, IGF-II and PDGF-AA may also stimulate osteoblast migration. Our results additionally suggest that TGF-beta and PDGF-BB may participate in the recruitment of osteoblasts during bone remodeling since both TGF-beta and PDGF-BB are found in bone matrix and could be released during osteoclastic bone resorption. They furthermore support a possible use of TGF-beta and PDGF-BB in growth factor-induced osteogenesis.

• Reilly JT
• Pathogenesis of idiopathic myelofibrosis: present status and future directions.
• Br J Haematol. 1994; 88: 1-8

• Fagundus DM, Leroy EC
• Cytokines and systemic sclerosis.
• Clin Dermatol. 1994; 12: 407-17

• Alioto RJ, Rosier RN, Burton RI, Puzas JE
• Comparative effects of growth factors on fibroblasts of Dupuytren's tissue and normal palmar fascia.
• J Hand Surg [Am]. 1994; 19: 442-52
• Display abstract

• Recent experimental evidence implicates various growth factors in the pathophysiology of Dupuytren's disease. This study describes a technique to produce an in vitro cell culture system from both normal palmar fascia and Dupuytren's fascia. The cells were separately exposed to basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta), and platelet-derived growth factor (PDGF), after which the effects of these growth factors on proliferation rate and collagen production were determined. Basic FGF and PDGF were found to be mitogenic for both cell types, and TGF-beta was a potent stimulator of collagen production for both cell types. There were quantitative and qualitative differences between the cell types, with Dupuytren cells being more metabolically active and more sensitive to the growth factors tested. We present a theoretical model based on previous investigations and incorporating the contribution of growth factors as it relates to the pathophysiology of Dupuytren's disease.

• Evain-Brion D
• [Growth factors: a pluripotent and misnamed family]
• Contracept Fertil Sex. 1994; 22: 523-7
• Display abstract

• Growth factors are a family of polypeptides with a major physiological role. They were first described for their mitogenic activity. However, these peptides have a wide spectrum of biological actions which include the regulation of tissue morphology, differentiation, movement and functional activity. They act via an autocrine or paracrine mechanism. They are characterized by their binding to specific receptors at the membrane level. Some of these receptors possess a kinase activity.

• Zhang YE
• [Progress of research on pathogenesis of glomerulosclerosis]
• Zhonghua Bing Li Xue Za Zhi. 1994; 23: 4-6

• Hom DB
• Growth factors and wound healing in otolaryngology.
• Otolaryngol Head Neck Surg. 1994; 110: 560-4
• Display abstract

• An immense amount of knowledge has been gained over the last decade in the realm of polypeptide growth factors. Only recently has this new information made an impact in otolaryngology. This article is a brief overview of peptide growth factors in relation to wound healing and otolaryngology.

• Peulve P, Laquerriere A, Paresy M, Hemet J, Tadie M
• Establishment of adult rat Schwann cell cultures: effect of b-FGF, alpha-MSH, NGF, PDGF, and TGF-beta on cell cycle.
• Exp Cell Res. 1994; 214: 543-50
• Display abstract

• Mitotically active Schwann cells isolated from adult rat sciatic nerve segments were cultivated, using a bivariate BrdU/DNA flow cytometry analysis, to test the effect of b-FGF (10 ng/ml), alpha-MSH (10 ng/ml), NGF (10 ng/ml), PDGF-AB (10 ng/ml), and TGF-beta 1 (10 ng/ml) on the cell cycle. Compared to control or cholera toxin-treated cultures, no significant differences (P < 0.05; Newmann-Keuls test) were observed in the proportion of G0G1 cells, S cells, G2M cells, and in the LI when alpha-MSH, NGF, PDGF-AB, or TGF-beta 1 were present. The S phase duration varied from 6.16 +/- 0.24 to 7.86 +/- 2.6 h, and the deduced potential doubling time was estimated at between 46.70 +/- 7.09 and 56.05 +/- 7.55 h. In contrast, when b-FGF was added to the culture, the cell cycle was significantly modified, and the proportion of G0G1 cells decreased from 68-77% to 59-64%, while the proportion of S cells increased from 14-16% to 24.0-26.4%. Although S phase duration was not significantly changed (6.02 +/- 0.36 h), the 1.7- to 2.8-fold LI increase reduced the potential doubling time to 25.99 +/- 6.13 h. We conclude from these results that only b-FGF-induced adult rat Schwann cells dramatically reenter in cell cycle and that this growth factor may be an axonally derived signal-promoting mitogenesis after nerve injury.

• See WA
• Commentary on growth factors: the bread-and-butter cytokines of urology.
• J Urol. 1994; 152: 1942-1942

• Miyazono K, Ichijo H, Heldin CH
• Transforming growth factor-beta: latent forms, binding proteins and receptors.
• Growth Factors. 1993; 8: 11-22

• Abboud HE
• Growth factors in glomerulonephritis.
• Kidney Int. 1993; 43: 252-67

• Igarashi A, Okochi H, Bradham DM, Grotendorst GR
• Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.
• Mol Biol Cell. 1993; 4: 637-45
• Display abstract

• Connective tissue growth factor (CTGF) is a cysteine-rich peptide that exhibits platelet-derived growth factor (PDGF)-like biological and immunological activities. CTGF is a member of a family of peptides that include serum-induced immediate early gene products, a v-src-induced peptide, and a putative avian transforming gene, nov. In the present study, we demonstrate that human foreskin fibroblasts produce high levels of CTGF mRNA and protein after activation with transforming growth factor beta (TGF-beta) but not other growth factors including PDGF, epidermal growth factor, and basic fibroblast growth factor. Because of the high level selective induction of CTGF by TGF-beta, it appears that CTGF is a major autocrine growth factor produced by TGF-beta-treated human skin fibroblasts. Cycloheximide did not block the large TGF-beta stimulation of CTGF gene expression, indicating that it is directly regulated by TGF-beta. Similar regulatory mechanisms appear to function in vivo during wound repair where there is a coordinate expression of TGF-beta 1 before CTGF in regenerating tissue, suggesting a cascade process for control of tissue regeneration and repair.

• Iles RK, Chard T
• Molecular insights into the structure and function of human chorionic gonadotrophin.
• J Mol Endocrinol. 1993; 10: 217-34

• Win KM et al.
• Mitogenic effect of transforming growth factor-beta 1 on human Ito cells in culture: evidence for mediation by endogenous platelet-derived growth factor.
• Hepatology. 1993; 18: 137-45
• Display abstract

• We assessed the effect of transforming growth factor-beta 1 on the proliferation of human Ito cells. Ito cells in their myofibroblastlike phenotype were grown from explants of human liver and were characterized with electron microscopy and positive immunostaining for desmin and smooth muscle alpha-actin. Transforming growth factor-beta 1 was mitogenic for human Ito cells whatever the culture conditions, although it was, as previously described, inhibitory of growth for rat Ito cells. The mitogenic effect of transforming growth factor-beta 1 was likely due to induction of autocrine platelet-derived growth factor chain secretion by Ito cells themselves because (a) the mitogenic effect of transforming growth factor-beta 1 was blocked by specific platelet-derived growth factor antibodies, (b) transforming growth factor-beta 1 increased platelet-derived growth factor-A chain messenger RNA expression and platelet-derived growth factor-AA secretion by human Ito cells and (c) human Ito cells expressed the alpha-type platelet-derived growth factor-A receptor messenger RNA. Exogenous platelet-derived growth factor-AA was also mitogenic for human Ito cells, mimicking the effect of transforming growth factor-beta 1. Our data suggest that results obtained with rat Ito cells must be extrapolated with caution to human ones. The mitogenic effect of transforming growth factor-beta 1 on human Ito cells probably has pathophysiological relevance because transforming growth factor-beta 1 has been demonstrated in vivo at sites of active liver fibrogenesis.

• Higaki S
• [Bone tumors and local factors]
• Nippon Seikeigeka Gakkai Zasshi. 1993; 67: 490-500

• Patthy L, Nikolics K
• Functions of agrin and agrin-related proteins.
• Trends Neurosci. 1993; 16: 76-81
• Display abstract

• Agrin, a molecule produced by motoneurons that induces the aggregation of nicotinic acetylcholine receptors (nAChRs), has recently been structurally characterized. Agrin-related proteins (ARPs) that arise from differential splicing are synthesized by neurons and muscle. The C-terminal region of agrin that instructs muscle to aggregate nAChRs contains three laminin A modules separated by epidermal growth factor-like modules. Alternative splicing in the laminin A modules leads to the formation of at least three ARPs that are devoid of nAChR-aggregating activity. In their N-terminal regions, both agrin and ARPs contain nine follistatin-related modules that, like those in follistatin and in another related protein, osteonectin, may have the capability to bind members of the transforming growth factor beta (TGF-beta) or platelet-derived growth factor (PDGF) families. This review proposes that these follistatin-like regions of agrin and ARPs might bind and localize growth factors, and thus provide a matrix-bound concentration of them. Beyond agrin's role in inducing AChR aggregation, the function of agrin and ARPs to provide a localized reservoir of growth factors could contribute to the formation and maintenance of the long-lasting synaptic architecture by specifying and limiting the area of influence of these molecules.

• Adamson ED
• Growth factors and their receptors in development.
• Dev Genet. 1993; 14: 159-64

• Offenbacher S
• Effects of dilantin on monocytic growth factors.
• J Periodontol. 1993; 64: 237-8

• Robinson CJ
• Growth factors: therapeutic advances in wound healing.
• Ann Med. 1993; 25: 535-8
• Display abstract

• Polypeptide growth factors regulate cellular processes involved in wound healing. Application of exogenous growth factors can modify the healing process and, with recombinant DNA technology, growth factors can now be made in sufficient quantity to be used therapeutically. Several growth factors are showing promising results in clinical trials, especially in cases of impaired healing, such as chronic ulcers. Preclinical studies indicate that further growth factors may have therapeutic potential in a wide range of wound-healing applications. The use of specifically designed and modified growth factors, growth-factor inhibitors, and sequential and combinatorial dosing regimes offer further possibilities for enhancing wound healing.

• Sporn MB, Roberts AB
• A major advance in the use of growth factors to enhance wound healing.
• J Clin Invest. 1993; 92: 2565-6

• Kikuchi K et al.
• Dermatofibrosarcoma protuberans: increased growth response to platelet-derived growth factor BB in cell culture.
• Biochem Biophys Res Commun. 1993; 196: 409-415
• Display abstract

• Dermatofibrosarcoma protuberans (DFSP) is a malignant tumor originating in the dermis. Although it is locally aggressive and recurs unless completely excised, it only rarely metastasizes. In the present study, we established 4 cultured DFSP cell strains, which were almost identical to normal skin fibroblasts when observed under a phase-contrast-microscope, and we observed their responses to various growth factors. DFSP cells showed significantly greater response to platelet-derived growth factor BB(PDGF BB) and transforming growth factor beta 1(TGF beta 1) than normal fibroblasts. We also determined upregulation of PDGF beta receptors in DFSP cells by both 125I PDGF-BB binding assay and immunoblotting analysis. These findings suggest that the interaction between the PDGF-B chain and the overexpression of PDGF beta receptors might play a role in the development of DFSP tumors.

• Johnson RJ
• Cytokine networks and the pathogenesis of glomerulonephritis.
• J Lab Clin Med. 1993; 121: 190-2

• Benahmed M et al.
• Transforming growth factor-beta(s) in the ovary.
• Ann N Y Acad Sci. 1993; 687: 13-9

• Oates TW, Rouse CA, Cochran DL
• Mitogenic effects of growth factors on human periodontal ligament cells in vitro.
• J Periodontol. 1993; 64: 142-8
• Display abstract

• Periodontal regeneration is thought to require the migration and proliferation of periodontal ligament cells. Evidence suggests that the polypeptide growth factors PDGF, IL-1, and TGF-beta are mediators of these cellular events in wound healing. The purpose of this study was to determine the effects of these growth factors on human periodontal ligament (PDL) cell mitogenesis, and to identify the regulatory influences of TGF-beta on the response to PDGF and IL-1. Confluent, quiescent human PDL cells were cultured in vitro and treated with the polypeptide growth factors PDGF-AA and -BB, IL-1 beta, and TGF-beta in both a dose and time-dependent manner. Mitogenic activity, as a measure of proliferative potential, was determined by the quantitation of 3H-thymidine incorporation during DNA synthesis. The results of this study demonstrated that both PDGF-AA and -BB enhance mitogenic activity in a dose-dependent manner over a concentration range of 1.0 to 50.0 ng/ml. IL-1 beta (0.01 to 1.0 pM) resulted in no mitogenic enhancement, and at high concentrations (10.0 to 100.0 pM) demonstrated an inhibitory effect. TGF-beta produced a significant increase (P < 0.01) in mitogenic activity (although relatively much less than PDGF) in a delayed, bimodal, dose-dependent manner over a concentration range of 0.01 to 20.0 ng/ml, with a maximal response at a concentration of 1.0 ng/ml. Additionally, incubation with TGF-beta at 1.0 ng/ml prior to the addition of PDGF significantly enhanced (P < 0.01) the mitogenic response to both PDGF-AA and PDGF-BB.(ABSTRACT TRUNCATED AT 250 WORDS)

• Hosgood G
• Wound healing. The role of platelet-derived growth factor and transforming growth factor beta.
• Vet Surg. 1993; 22: 490-5
• Display abstract

• Recent investigation into the mechanisms of wound healing has indicated the interaction of many substances, including several growth factors. The activity of platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta), are best defined. Both factors are secreted primarily from the alpha granules of platelets, but also from activated macrophages and fibroblasts. Investigation implicates the platelet as the initiator of wound healing, secreting PDGF, TGF-beta, and other factors that are chemotactic for monocytes, macrophages, and fibroblasts. Although their mode of action and degree of effect are different, both PDGF and TGF-beta increase the collagen content and early rate of gain of strength in wounds in normal and compromised tissue. In normal tissue, however, there is no long-term effect on wound outcome. The use of exogenous growth factors offers potential for chemical manipulation of the healing wound, particularly in tissues that are compromised, or where healing is abnormal.

• Reilly JT
• Pathogenesis of idiopathic myelofibrosis: role of growth factors.
• J Clin Pathol. 1992; 45: 461-4

• Swindells MB
• Structural similarity between transforming growth factor-beta 2 and nerve growth factor.
• Science. 1992; 258: 1160-1

• Ford J et al.
• Serum growth factors and oncoproteins in firefighters.
• Occup Med (Lond). 1992; 42: 39-42
• Display abstract

• Firefighters are potentially at increased risk for cancer and non-malignant respiratory disease due to their toxic exposures on the job. Growth factors and oncogene proteins are thought to play a role in the development of various malignancies and pulmonary fibrotic diseases. Therefore, a cohort of firefighters and matched controls have been screened for the presence of nine different growth factors and oncoproteins using an immunoblotting assay. Fourteen of the firefighters were found to be positive for beta-transforming growth factor (beta-TGF) related proteins compared to no positives in the controls (P = 0.0017). These results suggest that beta-TGF may be a possible biomarker for monitoring firefighters and other exposed workers for the potential development of cancer or non-malignant respiratory disease.

• Limper AH, Broekelmann TJ, Colby TV, Malizia G, McDonald JA
• Analysis of local mRNA expression for extracellular matrix proteins and growth factors using in situ hybridization in fibroproliferative lung disorders.
• Chest. 1991; 99: 5556-5556

• Ness JC, Morgan L, Outzen HC, Tapper D
• Specific growth factor activity identifies and predicts murine mammary tumor.
• J Surg Res. 1991; 50: 6-14
• Display abstract

• In milk from substrains of mice with varying incidences of developing mammary tumor, we have isolated a specific mitogenic activity, which is unique in that it identifies mice with mammary tumor and predicts those mice that will eventually develop mammary tumor. None of the milk samples from control mice, who never developed mammary tumor, contained this specific predictive mitogenic activity. Chemical characterization has shown this specific mitogenic activity to be acid- and heat-stable and resistant to reducing agents. Partial purification, by ion-exchange, high-performance liquid chromatography size-exclusion, and isoelectrofocusing techniques, of this specific mitogenic activity from milk of mice that had or eventually developed mammary tumor identifies several peptide growth factor components in a 6-10 kDa molecular weight range. Of known growth factors, radioassay techniques identify an insulin-like growth factor-1-like peptide as a major component. Small amounts of platelet-derived growth factor and transforming growth factor-beta activities also were present. Our results suggest that a subset of growth factors that are diagnostic of the presence of murine mammary tumor and predictive of eventual tumor development may be early indicators of the transition of a competent cell to a progressively malignant state. Similar studies of a secreted body fluid from women at risk for breast cancer may lead to the identification of a specific biologic tumor marker for breast cancer.

• Graves DT, Cochran DL
• Mesenchymal cell growth factors.
• Crit Rev Oral Biol Med. 1990; 1: 17-36

• McAvoy JW, Chamberlain CG
• Growth factors in the eye.
• Prog Growth Factor Res. 1990; 2: 29-43
• Display abstract

• In this review we report the distribution and functional significance of growth factors in the eye. Representatives of the major growth factor families are found in the eye: fibroblast growth factor, insulin and insulin-like growth factor, transforming growth factor-beta, platelet-derived growth factor, nerve growth factor, epidermal growth factor and colony-stimulating factor. There are numerous examples of their actions on ocular tissues in vitro and in some cases in vivo. The findings presented clearly illustrate that a growth factor can elicit different responses depending on the context of its action; the cell type involved, the concentration of the growth factor and the presence or absence of other growth factors can all influence the cellular response both quantitatively and qualitatively. The results of these studies in the eye are of general significance to our understanding of the role of growth factors in biological processes.

• Schaper W, Sharma HS, Quinkler W, Markert T, Wunsch M, Schaper J
• Molecular biologic concepts of coronary anastomoses.
• J Am Coll Cardiol. 1990; 15: 513-8
• Display abstract

• The discovery that collateral development after progressive coronary stenosis proceeds by means of DNA synthesis, mitosis and proliferation of endothelial and smooth muscle cells in preformed small interconnecting arterioles (canine heart) and capillaries (porcine heart) has stimulated research into the molecular mechanisms of vascular growth. Growth is tightly controlled under physiologic conditions, and several factors must act in concert to overcome control. Because the result of growth is a much larger orderly structure of complex design, we expect the existence of a genetic blueprint for its construction. Peptide growth factors have recently been isolated from a variety of organs, including the heart. We have provided experimental evidence that the heparin-binding growth factor beta-ECGF shows an increased transcription in growing pig collateral vessels. Because the chain of events probably originates in the ischemic cardiac myocyte, it appears logical to search there for the initiating factor. In addition to local production, growth factors can also be transported into ischemic myocardium by blood-borne cells. Monocytes adhere to altered endothelium in a potentially ischemic region and start to produce growth factors in situ. Platelets are rich sources of transforming growth factor-beta (TGF-beta), platelet-derived endothelial cell growth factor (PDECGF) and platelet-derived growth factor (PDGF), all of which are known angiogenic factors or mitogens.

• Franceschi C et al.
• Prostanoids as second messengers of polypeptide growth factors.
• Agents Actions. 1990; 29: 39-47
• Display abstract

• Prostaglandin H synthase (PGHs), also known as cyclooxygenase, is an unstable enzyme whose mRNA has an half life of 10 minutes. Some polypeptide factors have been reported to induce the enzyme in target cells. We have purified and characterized a component of animal sera which behaves as a potent inducer of human monocyte PGHs. This factor, called serum monocytotropic factor, has been identified in human platelets and it appears to be structurally and biochemically different from identified platelet factors, such as platelet derived growth factor (PDGF) and transforming growth factor beta (TGF-beta), while showing strong similarities to colony stimulating factor 1 (CSF-1), so far undetected in platelets. Moreover, we have shown, by immunoblot analysis, that CSF-1 behaves as a potent and specific inducer of monocyte PGHs. The hypothesis that prostanoids may be considered as second messengers of platelet CSF-1 like factor, as well as of other growth factors and that PGHs induction plays a pivotal role in this process, will be illustrated.

• Coombes RC, Barrett-Lee P, Luqmani Y
• Growth factor expression in breast tissue.
• J Steroid Biochem Mol Biol. 1990; 37: 833-6
• Display abstract

• We have studied mRNA levels for a variety of growth factors in biopsy specimens from malignant, benign and normal breast tissue. We found TGFb mRNA in all breast cancers and neoplastic breast tissues but the level of the TGFb mRNA were found to be higher in breast cancer (P = 0.01). TGFa mRNA was detected in a similar proportion of cancers as in neoplastic breast tissues but the TGFa receptor EGFR mRNA was detected in only 55% of breast cancers but in all non-neoplastic breast tissue tested. The presence of EGFR mRNA was inverted related to oestrogen receptor status and coexpression of TGFa and EGFR was observed in 28% of carcinomas, and significantly more commonly in ER negative tumours (P = 0.01). PDGF a and b chain transcripts coexisted in all normal and malignant breast tissue. Insulin-like growth factor II mRNA was present in all 15 samples of non-malignant breast tissue but in only 11 of 21 (52%) of carcinomas.

• Miyazono K, Takaku F
• Platelet-derived growth factors.
• Blood Rev. 1989; 3: 269-76
• Display abstract

• Blood platelets are a rich source of growth factors, including platelet-derived growth factor, platelet-derived endothelial cell growth factor, and transforming growth factor beta. Platelet-derived growth factor stimulates the growth of mesenchymal cells such as fibroblasts and vascular smooth muscle cells, whereas platelet-derived endothelial cell growth factor is a mitogen for vascular endothelial cells. Transforming growth factor beta is a bifunctional regulator of cellular growth, but acts as a potent inhibitor for most cell types. Most of the growth regulatory substances in platelets have been reported to reside in platelet alpha-granules, but platelet-derived endothelial cell growth factor appears to be present in platelet cytoplasm. These growth factors may act at sites of injury as wound hormones. Moreover, they play important roles for some pathological conditions such as atherosclerosis, myelofibrosis, connective tissue diseases, and neoplastic disorders.

• Reddi AH et al.
• Initiation of bone development by osteogenin and promotion by growth factors.
• Connect Tissue Res. 1989; 20: 303-12
• Display abstract

• The cellular and molecular basis of bone development and its regulation by differentiation and growth factors is an exciting area of current research. This article briefly reviews the historical progress in the isolation of osteogenin, a novel bone differentiation factor, and its modulation by well known growth factors. Endochondral bone development is a multistep sequential cascade and the process must be operationally dissected. It has been accomplished with the demineralized bone matrix-induced bone formation model. The reproducible development of cartilage and bone in an extraskeletal site permits the study of the initiation of the first cycle of endochondral bone formation and mineralization. Recent progress in the isolation of osteogenin, a specific bone differentiation factor, by heparin affinity chromatography permits the further investigation of the commitment and clonal expansion of the putative osteoprogenitor stem cells. Once initiated, bone formation is promoted by growth factors such as platelet derived growth factor, fibroblast growth factor, insulin like growth factor, transforming growth factor beta and a plethora of non specific cytokines. Finally bone development is further modulated by systemic hormones and nutrition and a host of physical signals including electrical, gravitational and mechanical forces.

• Dean DC
• Expression of the fibronectin gene.
• Am J Respir Cell Mol Biol. 1989; 1: 5-10
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• Fibronectin (FN) is an extracellular matrix protein that acts as a substrate for cell migration and adhesion during development. FN adheres to cells through a dimeric membrane protein, the FN receptor. Antibodies to FN and synthetic peptides that inhibit FN-receptor interaction inhibit gastrulation, block neural crest cell migration, arrest cardiac development, and block the fusion of myoblasts to form myotubes. FN and its receptor also appear to be important for lung development, where their expression coincides with the onset of branching morphogenesis, but drops to barely detectable levels in adult lung, indicating developmental specificity. FN expression is generally low in most adult tissues. However, synthesis is drastically increased during injury and wound healing, a process that in many ways mimics development. FN synthesis is also drastically increased in fibroproliferative lung lesions associated with major architectural changes in the lung. Expression of FN is regulated by a variety of growth factors and hormones. Several of these inducers (cAMP, transforming growth factor-beta, epidermal growth factor, platelet-derived growth factor, glucocorticoids, and vitamin D3) have themselves been implicated in developmental processes, and both cAMP and transforming growth factor-beta are known to stimulate expression of other matrix genes. One role of these hormones and growth factors in development may be to control expression of matrix genes, thereby controlling cell migration and adhesion. In the following report, the effect of hormones and growth factors on expression of the FN gene is reviewed.

• Gartner R
• [The significance of growth factors]
• Dtsch Med Wochenschr. 1986; 111: 1982-3

• Eisinger M, Marko O, Ogata S, Old LJ
• Growth regulation of human melanocytes: mitogenic factors in extracts of melanoma, astrocytoma, and fibroblast cell lines.
• Science. 1985; 229: 984-6
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• Melanocytes derived from fetal or adult skin do not propagate in vitro unless cultured in the presence of factors such as 12-O-tetradecanoylphorbol 13-acetate (TPA). In a search for physiological factors regulating the growth of melanocytes, extracts of various cultured cell types were tested. Factors produced by melanoma and astrocytoma cell lines support continued proliferation of melanocytes in the absence of TPA. WI-38, a fibroblast cell line derived from human embryonic lung, was the most active source of melanocyte growth factors. No melanocyte growth-promoting activity was found in extracts of cultured neuroblastoma, renal cancer, normal keratinocytes, or renal epithelium. Nerve growth factor, epidermal growth factor, melanocyte-stimulating hormone, transforming growth factor-beta, and platelet-derived growth factor did not have growth-promoting activity for melanocytes. The presence of melanocyte growth factors and TPA together resulted in the strongest mitogenic activity for melanocytes, permitting the recovery (at 20 days) of 4 to 20 times as many cells as in growth factor or TPA alone.

• Manso C
• [Growth factors]
• Acta Med Port. 1983; 4: 361-70

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