Platelet-derived growth factor (PDGF) is one among numerousgrowth factors that regulatecell growth 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 adimericglycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).
PDGF[1][2] is a potentmitogen for cells ofmesenchymal origin, includingfibroblasts,smooth muscle cells andglial cells. In both mouse and human, the PDGF signalling network consists of five ligands, PDGF-AA through -DD (including -AB), and two receptors, PDGFRalpha 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]
Recombinant PDGF 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.
Thereceptor for PDGF,PDGFR is classified as areceptor tyrosine kinase (RTK), a type ofcell surface receptor. 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-phosphorylation of several sites on theircytosolic domains, which serve to mediate binding of cofactors and subsequently activatesignal transduction, for example, through thePI3K pathway or throughreactive oxygen species (ROS)-mediated activation of theSTAT3 pathway.[11] Downstream effects of this include regulation ofgene expression and 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 oncogene is 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]
PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiatedmesenchyme and someprogenitor populations. 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 inembryonic development, cell proliferation, cell migration, andangiogenesis.[19] Over-expression of PDGF has been linked to severaldiseases such 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 checkpoints in 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]Wortmannin is 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]
PDGF was one of the firstgrowth factors characterized,[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]
Recombinant PDGF is used to help healchronic ulcers and 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).
Like many other growth factors that have been linked to disease, PDGF and its receptors have provided a market forreceptor antagonists to treat disease. Such antagonists include (but are not limited to) specificantibodies that target themolecule of interest, which act only in a neutralizing manner.[31]
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, fixing 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‐glycosaminoglycan scaffolds.[37]
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^Kumar, Vinay (2010).Robbins and Coltran Pathologic Basis of Disease. China: Elsevier. pp. 88–89.ISBN978-1-4160-3121-5.
^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.
^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.Bibcode:1989BBRC..165.1198T.doi:10.1016/0006-291X(89)92729-0.PMID2610687.
^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.
^abAlvarez RH, Kantarjian 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.
^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
^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.
