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Platelet-derived growth factor

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"PDGF" redirects here. For the space hardware, seePower Data Grapple Fixture.

Platelet-derived growth factor(PDGF) is one among numerousgrowth factorsthat regulatecellgrowth anddivision.In particular, PDGF plays a significant role inblood vessel formation,the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well aschemotaxis,the directed migration, of mesenchymal cells. Platelet-derived growth factor is adimericglycoproteinthat can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).

Platelet-derived growth factor
Platelet-derived growth factor BB monomer, Human
Identifiers
SymbolPDGF
PfamPF00341
InterProIPR000072
PROSITEPDOC00222
SCOP21pdg/SCOPe/SUPFAM
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

PDGF[1][2]is a potentmitogenfor cells ofmesenchymalorigin, includingfibroblasts,smooth muscle cellsandglial cells.In both mouse and human, the PDGF signalling network consists of five ligands, PDGF-AA through -DD (including -AB), and two receptors, PDGFR Alpha and PDGFRbeta. All PDGFs function as secreted, disulphide-linked homodimers, but only PDGFA and B can form functional heterodimers.

Though PDGF is synthesized,[3]stored (in the Alpha granules ofplatelets),[4]and released by platelets upon activation, it is also produced by other cells including smooth muscle cells, activated macrophages, and endothelial cells[5]

RecombinantPDGF is used in medicine to help healchronic ulcers,to heal ocular surface diseases and in orthopedic surgery and periodontics as an alternative to bone autograft to stimulate bone regeneration and repair.

Types and classification

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There are five differentisoformsof PDGF that activate cellular response through two differentreceptors.Knownligandsinclude: PDGF-AA (PDGFA), -BB (PDGFB), -CC (PDGFC), and -DD (PDGFD), and -AB (aPDGFAandPDGFBheterodimer).The ligands interact with the twotyrosine kinase receptormonomers, PDGFRα (PDGFRA) and -Rβ (PDGFRB).[6]The PDGF family also includes a few other members of the family, including theVEGF sub-family.[7]

Mechanisms

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Thereceptorfor PDGF,PDGFRis classified as areceptor tyrosine kinase(RTK), a type ofcell surfacereceptor. Two types of PDGFRs have been identified: Alpha -type and beta-type PDGFRs.[8]The Alpha type binds to PDGF-AA, PDGF-BB and PDGF-AB, whereas the beta type PDGFR binds with high affinity to PDGF-BB and PDGF-AB.[9] PDGF binds to the PDGFR ligand binding pocket located within the second and third immunoglobulin domains.[10]Upon activation by PDGF, these receptors dimerise, and are "switched on" by auto-phosphorylationof several sites on theircytosolicdomains, which serve to mediate binding of cofactors and subsequently activatesignal transduction,for example, through thePI3Kpathway or throughreactive oxygen species (ROS)-mediated activation of theSTAT3pathway.[11]Downstream effects of this include regulation ofgene expressionand thecell cycle. The role of PI3K has been investigated by several laboratories. Accumulating data suggests that, while this molecule is, in general, part of growth signaling complex, it plays a more profound role in controlling cell migration.[12] The different ligand isoforms have variable affinities for the receptor isoforms, and the receptor isoforms may variably form hetero- or homo- dimers. This leads to specificity of downstream signaling. It has been shown that thesis oncogeneis derived from the PDGF B-chaingene.PDGF-BB is the highest-affinity ligand for the PDGFR-beta; PDGFR-beta is a key marker of hepatic stellate cell activation in the process offibrogenesis.[citation needed]

Function

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PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiatedmesenchymeand someprogenitorpopulations. During later maturation stages, PDGF signalling has been implicated in tissue remodelling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialised mesenchymal and migratory cell types, both during development and in the adult animal.[13][14][15]Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C)[16][17]which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis.[18]

PDGF plays a role inembryonicdevelopment, cell proliferation, cell migration, andangiogenesis.[19]Over-expression of PDGF has been linked to severaldiseasessuch asatherosclerosis,fibrotic disorders and malignancies. Synthesis occurs due to external stimuli such as thrombin, low oxygen tension, or other cytokines and growth factors.[20]

PDGF is a required element in cellular division forfibroblasts,a type of connective tissue cell that is especially prevalent in wound healing.[20]In essence, the PDGFs allow a cell to skip theG1 checkpointsin order to divide.[21]It has been shown that in monocytes-macrophages and fibroblasts, exogenously administered PDGF stimulates chemotaxis, proliferation, and gene expression and significantly augmented the influx of inflammatory cells and fibroblasts, accelerating extracellular matrix and collagen formation and thus reducing the time for the healing process to occur.[22]

In terms of osteogenic differentiation of mesenchymal stem cells, comparing PDGF to epidermal growth factor (EGF), which is also implicated in stimulating cell growth, proliferation, and differentiation,[23]MSCs were shown to have stronger osteogenic differentiation into bone-forming cells when stimulated by epidermal growth factor (EGF) versus PDGF. However, comparing the signaling pathways between them reveals that the PI3K pathway is exclusively activated by PDGF, with EGF having no effect. Chemically inhibiting the PI3K pathway in PDGF-stimulated cells negates the differential effect between the two growth factors, and actually gives PDGF an edge in osteogenic differentiation.[23]Wortmanninis a PI3K-specific inhibitor, and treatment of cells with Wortmannin in combination with PDGF resulted in enhanced osteoblast differentiation compared to just PDGF alone, as well as compared to EGF.[23]These results indicate that the addition of Wortmannin can significantly increase the response of cells into an osteogenic lineage in the presence of PDGF, and thus might reduce the need for higher concentrations of PDGF or other growth factors, making PDGF a more viable growth factor for osteogenic differentiation than other, more expensive growth factors currently used in the field such as BMP2.[24]

PDGF is also known to maintain proliferation ofoligodendrocyte progenitor cells(OPCs).[25][26]It has also been shown that fibroblast growth factor (FGF) activates a signaling pathway that positively regulates the PDGF receptors in OPCs.[27]

History

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PDGF was one of the firstgrowth factorscharacterized,[28]and has led to an understanding of the mechanism of many growth factorsignaling pathways.[citation needed]The first engineered dominant negative protein was designed to inhibit PDGF[29]

Medicine

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RecombinantPDGF is used to help healchronic ulcersand in orthopedic surgery and periodontics to stimulate bone regeneration and repair.[30]PDGF may be beneficial when used by itself or especially in combination with other growth factors to stimulate soft and hard tissue healing (Lynch et al. 1987, 1989, 1991, 1995).

Research

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Like many other growth factors that have been linked to disease, PDGF and its receptors have provided a market forreceptor antagoniststo treat disease. Such antagonists include (but are not limited to) specificantibodiesthat target themoleculeof interest, which act only in a neutralizing manner.[31]

The "c-Sis"oncogeneis derived from PDGF.[26][32]

Age related downregulation of the PDGF receptor on islet beta cells has been demonstrated to prevent islet beta cell proliferation in both animal and human cells and its re-expression triggered beta cell proliferation and corrected glucose regulation via insulin secretion.[33][34]

A non-viral PDGF "bio patch" can regenerate missing or damaged bone by delivering DNA in a nano-sized particle directly into cells via genes. Repairing bone fractures, fi xing craniofacial defects and improving dental implants are among potential uses. The patch employs a collagen platform seeded with particles containing the genes needed for producing bone. In experiments, new bone fully covered skull wounds in test animals and stimulated growth in human bone marrowstromal cells.[35][36]

The addition of PDGF at specific time‐points has been shown to stabilise vasculature in collagen‐glycosaminoglycanscaffolds.[37]

Family members

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Human genes encoding proteins that belong to the platelet-derived growth factor family include:

See also

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References

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  1. ^Hannink M, Donoghue DJ (1989). "Structure and function of platelet-derived growth factor (PDGF) and related proteins".Biochim. Biophys. Acta.989(1): 1–10.doi:10.1016/0304-419x(89)90031-0.PMID2546599.
  2. ^Heldin CH (1992)."Structural and functional studies on platelet-derived growth factor".EMBO J.11(12): 4251–4259.doi:10.1002/j.1460-2075.1992.tb05523.x.PMC556997.PMID1425569.
  3. ^Minarcik, John."Global Path Course: Video".Archived fromthe originalon 2018-09-29.Retrieved2011-06-27.
  4. ^"The Basic Biology of Platelet Growth Factors".September 2004.Retrieved2014-05-08.
  5. ^Kumar, Vinay (2010).Robbins and Coltran Pathologic Basis of Disease.China: Elsevier. pp. 88–89.ISBN978-1-4160-3121-5.
  6. ^Fredriksson, Linda; Li, Hong; Eriksson, Ulf (August 2004). "The PDGF family: four gene products form five dimeric isoforms".Cytokine & Growth Factor Reviews.15(4): 197–204.doi:10.1016/j.cytogfr.2004.03.007.PMID15207811.
  7. ^Tischer, Edmund; Gospodarowicz, Denis; Mitchell, Richard; Silva, Maria; Schilling, James; Lau, Kenneth; Crisp, Tracey; Fiddes, John C.; Abraham, Judith A. (December 1989). "Vascular endothelial growth factor: A new member of the platelet-derived growth factor gene family".Biochemical and Biophysical Research Communications.165(3): 1198–1206.doi:10.1016/0006-291X(89)92729-0.PMID2610687.
  8. ^Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M, Pierce J, Aaronson S (1989)."Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes".Science.243(4892): 800–804.Bibcode:1989Sci...243..800M.doi:10.1126/science.2536956.PMID2536956.
  9. ^Heidaran MA, Pierce JH, Yu JC, Lombardi D, Artrip JE, Fleming TP, Thomason A, Aaronson SA (25 October 1991)."Role of Alpha beta receptor heterodimer formation in beta platelet-derived growth factor (PDGF) receptor activation by PDGF-AB".J. Biol. Chem.266(30): 20232–7.doi:10.1016/S0021-9258(18)54914-0.PMID1657917.
  10. ^Heidaran MA, Pierce JH, Jensen RA, Matsui T, Aaronson SA (5 November 1990)."Chimeric Alpha - and beta-platelet-derived growth factor (PDGF) receptors define three immunoglobulin-like domains of the Alpha -PDGF receptor that determine PDGF-AA binding specificity".J. Biol. Chem.265(31): 18741–18744.doi:10.1016/S0021-9258(17)30572-0.PMID2172231.
  11. ^Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH (December 2013)."12/15-Lipoxygenase Contributes to Platelet-derived Growth Factor-induced Activation of Signal Transducer and Activator of Transcription 3".J. Biol. Chem.288(49): 35592–35603.doi:10.1074/jbc.M113.489013.PMC3853304.PMID24165129.
  12. ^Yu JC, Li W, Wang LM, Uren A, Pierce JH, Heidaran MA (1995)."Differential requirement of a motif within the carboxyl-terminal domain of Alpha -platelet-derived growth factor ( Alpha PDGF) receptor for PDGF focus forming activity chemotaxis, or growth".J. Biol. Chem.270(13): 7033–7036.doi:10.1074/jbc.270.13.7033.PMID7706238.
  13. ^Ataliotis, P; Symes, K; Chou, MM; Ho, L; Mercola, M (September 1995). "PDGF signalling is required for gastrulation of Xenopus laevis".Development.121(9): 3099–3110.doi:10.1242/dev.121.9.3099.PMID7555734.
  14. ^Symes, K; Mercola, M (3 September 1996)."Embryonic mesoderm cells spread in response to platelet-derived growth factor and signaling by phosphatidylinositol 3-kinase".Proceedings of the National Academy of Sciences of the United States of America.93(18): 9641–4.Bibcode:1996PNAS...93.9641S.doi:10.1073/pnas.93.18.9641.PMC38481.PMID8790383.
  15. ^Hoch RV, Soriano P (2003). "Roles of PDGF in animal development".Development.130(20): 4769–4784.doi:10.1242/dev.00721.PMID12952899.S2CID24124211.
  16. ^Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U (1996)."Vascular endothelial growth factor B, a novel growth factor for endothelial cells".Proc. Natl. Acad. Sci. U.S.A.93(6): 2567–2581.Bibcode:1996PNAS...93.2576O.doi:10.1073/pnas.93.6.2576.PMC39839.PMID8637916.
  17. ^Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996)."A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases".EMBO J.15(2): 290–298.doi:10.1002/j.1460-2075.1996.tb00359.x.PMC449944.PMID8617204.
  18. ^Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG (1993). "Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14".Oncogene.8(4): 925–931.PMID7681160.
  19. ^"PDGF Pathways".Archived fromthe originalon 2006-11-13.Retrieved2007-11-17.
  20. ^abAlvarez RH, Kantar gian HM, Cortes JE (September 2006). "Biology of platelet-derived growth factor and its involvement in disease".Mayo Clin. Proc.81(9): 1241–1257.doi:10.4065/81.9.1241.PMID16970222.
  21. ^Song G, Ouyang G, Bao S (2005)."The activation of Akt/PKB signaling pathway and cell survival".J. Cell. Mol. Med.9(1): 59–71.doi:10.1111/j.1582-4934.2005.tb00337.x.PMC6741304.PMID15784165.
  22. ^Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A (April 1991). "Role of platelet-derived growth factor in wound healing".J. Cell. Biochem.45(4): 319–326.doi:10.1002/jcb.240450403.PMID2045423.S2CID8539542.
  23. ^abcKratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M (June 2005). "Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation".Science.308(5727): 1472–1477.Bibcode:2005Sci...308.1472K.doi:10.1126/science.1107627.PMID15933201.S2CID10690497.
  24. ^Hayashi, A. The New Standard of Care for Nonunions?. AAOS Now. 2009.
  25. ^Barres BA,Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992). "Cell Death and Control of Cell Survival in the Oligodendrocyte Lineage".Cell.70(1): 31–46.doi:10.1016/0092-8674(92)90531-G.PMID1623522.S2CID11529297.
  26. ^abProto-Oncogene+Proteins+c-sisat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
  27. ^McKinnon RD, Matsui T, Dubois-Dalcq M, Aaronson SA (November 1990). "FGF modulates the PDGF-driven pathway of oligodendrocyte development".Neuron.5(5): 603–614.doi:10.1016/0896-6273(90)90215-2.PMID2171589.S2CID23026544.
  28. ^Paul D, Lipton A, Klinger I (1971)."Serum factor requirements of normal and simian virus 40-transformed 3T3 mouse fibroplasts".Proc Natl Acad Sci U S A.68(3): 645–652.Bibcode:1971PNAS...68..645P.doi:10.1073/pnas.68.3.645.PMC389008.PMID5276775.
  29. ^Mercola, M; Deininger, P L; Shamah, S M; Porter, J; Wang, C Y; Stiles, C D (1 December 1990)."Dominant-negative mutants of a platelet-derived growth factor gene".Genes & Development.4(12b): 2333–2341.doi:10.1101/gad.4.12b.2333.PMID2279701.
  30. ^Friedlaender GE, Lin S, Solchaga LA, Snel LB, Lynch SE (2013). "The role of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in orthopaedic bone repair and regeneration".Current Pharmaceutical Design.19(19): 3384–3390.doi:10.2174/1381612811319190005.PMID23432673.Demonstration of the safety and efficacy of rhPDGF-BB in the healing of chronic foot ulcers in diabetic patients and regeneration of alveolar (jaw) bone lost due to chronic infection from periodontal disease has resulted in two FDA-approved products based on this molecule
  31. ^Shulman T, Sauer FG, Jackman RM, Chang CN, Landolfi NF (July 1997)."An antibody reactive with domain 4 of the platelet-derived growth factor beta receptor allows BB binding while inhibiting proliferation by impairing receptor dimerization".J. Biol. Chem.272(28): 17400–17404.doi:10.1074/jbc.272.28.17400.PMID9211881.
  32. ^McClintock JT, Chan IJ, Thaker SR, Katial A, Taub FE, Aotaki-Keen AE, Hjelmeland LM (1992). "Detection of c-sis proto-oncogene transcripts by direct enzyme-labeled cDNA probes and in situ hybridization".In Vitro Cell Dev Biol.28A(2): 102–108.doi:10.1007/BF02631013.PMID1537750.S2CID9958016.
  33. ^"Researchers make older beta cells act young again".Eurekalert.org. 2011-10-12.Retrieved2013-12-28.
  34. ^"New Stanford molecular target for diabetes treatment discovered".Med.stanford.edu – Stanford University School of Medicine. 2011-10-12. Archived fromthe originalon 2013-10-21.Retrieved2013-12-28.
  35. ^Elangovan, S.; d'Mello, S. R.; Hong, L.; Ross, R. D.; Allamargot, C.; Dawson, D. V.; Stanford, C. M.; Johnson, G. K.; Sumner, D. R.; Salem, A. K. (2013-11-12)."Bio patch can regrow bone for dental implants and craniofacial defects".Biomaterials.35(2). KurzweilAI: 737–747.doi:10.1016/j.biomaterials.2013.10.021.PMC3855224.PMID24161167.Retrieved2013-12-28.
  36. ^Elangovan S, D'Mello SR, Hong L, Ross RD, Allamargot C, Dawson DV, Stanford CM, Johnson GK, Sumner DR, Salem AK (2014)."The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor".Biomaterials.35(2): 737–747.doi:10.1016/j.biomaterials.2013.10.021.PMC3855224.PMID24161167.
  37. ^Amaral, Ronaldo Jose Farias Correa; Cavanagh, Brenton; O'Brien, Fergal Joseph; Kearney, Cathal John (16 December 2018)."Platelet-derived growth factor stabilises vascularisation in collagen-glycosaminoglycan scaffolds".Journal of Tissue Engineering and Regenerative Medicine.13(2): 261–273.doi:10.1002/term.2789.PMID30554484.S2CID58767660.
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