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Platelet-derived growth factor
Platelet-derived growth factor
Platelet-derived growth factor
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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

Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood 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 as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein 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 potent mitogen for cells of mesenchymal origin, including fibroblasts, smooth muscle cells and glial 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 of platelets),[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 heal chronic 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 different isoforms of PDGF that activate cellular response through two different receptors. Known ligands include: PDGF-AA (PDGFA), -BB (PDGFB), -CC (PDGFC), and -DD (PDGFD), and -AB (a PDGFA and PDGFB heterodimer). The ligands interact with the two tyrosine kinase receptor monomers, PDGFRα (PDGFRA) and -Rβ (PDGFRB).[6] The PDGF family also includes a few other members of the family, including the VEGF sub-family.[7]

Mechanisms

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The receptor for PDGF, PDGFR is classified as a receptor tyrosine kinase (RTK), a type of cell 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 their cytosolic domains, which serve to mediate binding of cofactors and subsequently activate signal transduction, for example, through the PI3K pathway or through reactive oxygen species (ROS)-mediated activation of the STAT3 pathway.[11] Downstream effects of this include regulation of gene expression and the cell 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 the sis oncogene is derived from the PDGF B-chain gene. 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 of fibrogenesis.[citation needed]

Function

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PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor 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 in embryonic development, cell proliferation, cell migration, and angiogenesis.[19] Over-expression of PDGF has been linked to several diseases such as atherosclerosis, 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 for fibroblasts, a type of connective tissue cell that is especially prevalent in wound healing.[20] In essence, the PDGFs allow a cell to skip the G1 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 of oligodendrocyte 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

[edit]

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

Medicine

[edit]

Recombinant PDGF is used to help heal chronic 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).

Research

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Like many other growth factors that have been linked to disease, PDGF and its receptors have provided a market for receptor antagonists to treat disease. Such antagonists include (but are not limited to) specific antibodies that target the molecule of interest, which act only in a neutralizing manner.[31]

The "c-Sis" oncogene is 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, 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 marrow stromal cells.[35][36]

The addition of PDGF at specific time‐points has been shown to stabilise vasculature in collagen‐glycosaminoglycan scaffolds.[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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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Platelet-derived growth factor

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Platelet-derived growth factor (PDGF) is a family of dimeric glycoproteins composed of four polypeptide chains (A, B, C, and D) that assemble into five bioactive isoforms, acting as potent mitogens, chemoattractants, and regulators of cell survival for mesenchymal-origin cells such as fibroblasts, cells, and . Discovered in 1974 by Russell Ross and colleagues at the while studying the of , PDGF was initially identified as a soluble factor released from the alpha granules of activated platelets that promotes the proliferation and migration of arterial cells, contributing to the formation of atherosclerotic lesions. Subsequent research revealed its broader production by various cell types, including endothelial cells, macrophages, and fibroblasts, particularly at sites of injury or . Structurally, all PDGF isoforms share a conserved C-terminal cystine-knot domain stabilized by bonds, with molecular weights around 25–30 for the mature dimers; the A and B chains, encoded by genes on chromosomes 7 and 22 respectively, can form both homodimers (PDGF-AA, PDGF-BB) and the heterodimer PDGF-AB, whereas the more recently identified C and D chains (discovered in the late and early ) primarily form homodimers (PDGF-CC, PDGF-DD) and include an N-terminal that requires proteolytic cleavage by proteases like or for activation and secretion. These structural variations influence ligand-receptor specificity and , with PDGF-A and -B showing about 50% sequence identity to each other, while PDGF-C and -D share roughly 25% identity with A/B but 50% with one another. PDGF signals through two homologous cell-surface receptor kinases, PDGFRα (encoded on 4q12) and PDGFRβ (encoded on 5q32), which undergo dimerization (αα, αβ, or ββ) upon binding, leading to autophosphorylation and activation of downstream pathways including PI3K/AKT for cell survival and MAPK/ERK for proliferation and migration. In normal physiology, PDGF is indispensable for embryonic development—such as vasculogenesis, , and cell migration—and adult tissue , including where it recruits to stabilize new vessels and stimulates production. Dysregulated PDGF signaling, however, drives pathological conditions like (e.g., in kidney and ), via excessive smooth muscle proliferation, and cancers such as gliomas and sarcomas through autocrine loops that promote tumor growth and . Therapeutically, PDGF inhibitors like target overactive receptors in certain malignancies, highlighting its clinical significance.

Discovery and History

Initial Discovery

Platelet-derived growth factor (PDGF) was first identified in the early 1970s as a key mitogen released from platelets, stimulating the proliferation of arterial smooth muscle cells (SMCs) in vitro. In 1974, Russell Ross and colleagues at the University of Washington demonstrated that dialyzed serum derived from clotted primate blood promoted robust SMC growth, whereas serum from recalcified platelet-poor plasma exhibited significantly reduced mitogenic activity. Experiments revealed that adding platelets or a platelet-free supernatant from thrombin-activated platelets to the plasma-derived serum restored its proliferative effects to levels comparable to whole blood serum, pinpointing the platelets as the primary source of the growth-promoting factor. This discovery was motivated by investigations into the cellular basis of atherosclerosis, where SMC proliferation plays a central role. Subsequent cell culture studies using platelet extracts further characterized the factor's potency. Extracts from human or primate platelets were applied to quiescent cultures of SMCs and fibroblasts, where they induced and cell division, as measured by incorporation of tritiated . For instance, in BALB/c 3T3 fibroblasts, platelet-derived material at concentrations equivalent to 1% whole serum triggered a marked increase in within 24 hours, highlighting its role as a competence factor for initiating the . These assays established the term "platelet-derived growth factor" (PDGF) to describe this cationic protein, distinct from other serum components like plasma growth-promoting activity. Between 1974 and 1978, initial purification efforts isolated PDGF from outdated , confirming its localization within platelet alpha granules—the dense storage organelles released upon activation. Using techniques such as , ion-exchange , gel filtration, and sodium dodecyl sulfate-polyacrylamide , researchers achieved up to 800,000-fold purification. The native protein was identified as a disulfide-bonded dimer with a molecular weight of approximately 30,000 Da, comprising two distinct polypeptide chains of about 14,000 Da and 17,000 Da. Early biochemical assays on glial cells and fibroblasts showed that purified PDGF at nanogram concentrations (e.g., 4 ng/mL) stimulated equivalently to 1% serum, underscoring its high .

Key Milestones

In 1979, key purification and partial characterization work by Carl-Henrik Heldin's group confirmed PDGF as a distinct mitogen released from alpha granules in platelets, demonstrating its role in stimulating connective tissue cell growth. The cloning of PDGF genes marked a pivotal advancement in the 1980s. In 1984, the PDGF-B chain gene was cloned by Heldin and colleagues, revealing its sequence homology to the v-sis oncogene from simian sarcoma virus and confirming PDGF as a dimeric protein composed of A and B chains. This was followed in 1986 by the cloning of the PDGF-A chain by Christer Betsholtz et al., which established the existence of homodimeric and heterodimeric isoforms and localized the gene to chromosome 7. Concurrently, in 1986, Yarden et al. cloned the PDGF receptor (PDGFR), identifying it as a transmembrane tyrosine kinase and elucidating its dimerization upon ligand binding, which laid the foundation for understanding PDGF signaling specificity. By the late 1980s, PDGF was recognized as the founding member of the PDGF/VEGF family, following the 1989 cloning of (VEGF) by Leung et al., which highlighted shared structural features such as the cystine-knot motif and conserved receptor-binding domains across these dimeric proteins. In the early 1990s, structural elucidation advanced with the 1992 determination of the of human PDGF-BB by Olofsson et al., revealing a novel antiparallel disulfide-linked homodimer with two protruding receptor-binding regions, which provided insights into its mitogenic potency and informed subsequent isoform comparisons. Parallel animal model studies emerged around this time; the first PDGF mice, reported in 1994 by Levéen et al. and Soriano, demonstrated lethal perinatal phenotypes in PDGF-B and PDGFR-β null mutants, including renal glomerulogenesis failure and cardiovascular defects, underscoring PDGF's essential role in vascular development and recruitment. The PDGF family was completed with the discovery of two additional chains in the early 2000s. PDGF-C was identified in 2000 by three independent groups through homology-based searches and expression studies, revealing it as a novel primarily activating PDGFRα. PDGF-D was cloned in 2001, showing specificity for PDGFRβ and requiring proteolytic activation similar to PDGF-C. These findings expanded the understanding of PDGF diversity and signaling specificity.

Structure and Classification

Molecular Composition

Platelet-derived (PDGF) consists of -linked homo- or heterodimers formed by two of four possible polypeptide chains, designated A, B, C, or D, resulting in a mature protein with a molecular weight of approximately 28-31 . These dimers are stabilized by covalent bonds, which are essential for the structural integrity and bioactivity of the . The four PDGF chains are encoded by separate genes located at distinct chromosomal positions in the : PDGFA on 7p22.3, PDGFB on 22q13.1, PDGFC on 4q32.1, and PDGFD on 11q22.3. The primary structure of each PDGF chain precursor comprises an N-terminal of 18-22 , followed by a prodomain and a central domain of about 100-140 residues. For PDGF-C and PDGF-D, the prodomain includes an N-terminal that maintains latency until proteolytic cleavage. This central domain contains eight highly conserved cysteine residues that form a characteristic cystine-knot motif, including three intermolecular disulfide bonds linking the two chains and two intramolecular bonds within each chain to maintain the dimeric fold. The is cleaved co-translationally during translocation into the , yielding the pro-PDGF form. Post-translational modifications are critical for PDGF maturation and include proteolytic to remove prodomains and, in some cases, N-linked . For PDGF-A and PDGF-B chains, intracellular cleavage by furin-like proprotein convertases at dibasic motifs (e.g., RRKR for A-chain, RGRR for B-chain) generates active dimers stored in platelet alpha-granules. In contrast, PDGF-C and PDGF-D are secreted as latent complexes with their prodomains intact and require extracellular proteolytic activation by serine proteases such as , tissue plasminogen activator (tPA), or plasminogen activator (uPA). occurs at specific residues in certain chains, such as three N-linked sites (Asn25, Asn55, Asn254) in PDGF-C, which may influence stability and , though it is absent or minimal in PDGF-A. Dimerization is represented simply as the covalent linkage of two monomeric chains, such as A + B → PDGF-AB, facilitated by the conserved cysteines in the domains. These structural elements form the foundational building blocks for the various PDGF isoforms.

Isoforms and Family Members

Platelet-derived (PDGF) exists in five principal dimeric isoforms, formed by disulfide-linked combinations of four distinct polypeptide chains: PDGF-A, PDGF-B, PDGF-C, and PDGF-D. These isoforms include the homodimers PDGF-AA, PDGF-BB, PDGF-CC, and PDGF-DD, as well as the heterodimer PDGF-AB. The chains share structural homology, particularly in their conserved C-terminal domains, but exhibit varied tissue-specific expression patterns that contribute to their functional diversity. For instance, PDGF-BB is the predominant isoform stored in platelet alpha-granules and released upon , while PDGF-AA is widely expressed in epithelial and mesenchymal cells during development and repair processes. The isoforms display distinct ligand specificities for the two PDGF receptor tyrosine kinases, PDGFRα and PDGFRβ, which can form homodimers (αα, ββ) or heterodimers (αβ). PDGF-AA binds exclusively to PDGFRαα, PDGF-AB binds to both PDGFRαα and αβ, PDGF-BB binds to all three receptor dimers (αα, αβ, ββ), PDGF-CC binds to PDGFRαα and αβ, and PDGF-DD binds solely to PDGFRββ. This differential binding enables isoform-specific activation of signaling pathways tailored to cellular contexts. PDGF belongs to the PDGF/VEGF superfamily, sharing a characteristic cystine-knot fold in its domain—a structural motif involving three intramolecular bonds that stabilizes the dimeric for receptor interaction. This evolutionary relationship with vascular endothelial growth factors (VEGFs), including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and (PlGF), underscores their common ancestry, despite VEGFs primarily promoting and through distinct receptor interactions. Homologs of PDGF are conserved across the animal kingdom, with PDGF/VEGF-like factors identified in such as (e.g., PVF1, PVF2, PVF3) and , where they regulate and patterning during development. These non-mammalian variants retain the cystine-knot structure and similar receptor-binding properties, highlighting the ancient origins of the superfamily.

Biological Mechanisms

Receptor Interactions

Platelet-derived growth factor (PDGF) ligands exert their effects by binding to two closely related cell-surface receptor kinases: platelet-derived growth factor receptor alpha (PDGFRα) and platelet-derived growth factor receptor beta (PDGFRβ). These receptors belong to the class III of receptor kinases and possess an extracellular -binding domain composed of five immunoglobulin-like domains, a single transmembrane helix, and an intracellular kinase domain. Upon binding, PDGFRα and PDGFRβ can assemble into three possible dimeric complexes—homodimers αα and ββ, or the heterodimer αβ—each capable of transducing distinct signals depending on the involved. The binding specificities of the five dimeric PDGF isoforms (AA, BB, AB, CC, DD) to these receptor dimers vary, with PDGF-BB exhibiting the broadest and highest affinity for all three combinations, while other isoforms show more restricted preferences. For instance, PDGF-AA and PDGF-CC bind exclusively to PDGFRα homodimers and αβ heterodimers, PDGF-AB binds to αα and αβ, and PDGF-DD binds only to αβ and ββ. These affinities have been quantified through binding assays, with dissociation constants (K_d) typically in the low nanomolar range for high-affinity interactions, such as K_d ≈ 0.1–1 nM for PDGF-BB to PDGFRββ. The following table summarizes the key binding specificities:
PDGF IsoformPDGFRααPDGFRαβPDGFRββ
AAHighHighNone
BBHighHighHigh
ABHighHighLow/None
CCHighHighNone
DDNoneHighHigh
This differential binding allows for isoform-specific activation of receptor dimers in various cellular contexts. Ligand binding to the extracellular domains of PDGFRs induces receptor dimerization, a critical step in activation. The dimeric PDGF ligands bridge two receptor molecules, primarily involving immunoglobulin-like domains 2 and 3 (D2 and D3) in the binding interface, which stabilizes the dimer and positions the intracellular domains in close proximity. This conformational change triggers trans-autophosphorylation of specific residues in the kinase domains and juxtamembrane regions, initiating the receptor's catalytic activity without requiring additional cofactors. Structural studies, including cryo-electron of the full-length PDGFRβ dimer bound to PDGF-BB, have revealed that ligand-induced dimerization involves a 2:2 (two ligands to two receptors) and highlights key hydrophobic and electrostatic interactions at the , such as the burial of a large hydrophobic surface area upon complex formation. Earlier crystallographic analyses of the extracellular domains, such as the 2010 structure of PDGF-B with the D1-D3 domains of PDGFRβ (PDB: 3MJG), further illustrate the dynamic rearrangements in the ligand's L1 loop upon receptor engagement. In terms of cellular distribution, PDGFRα is predominantly expressed on mesenchymal progenitor cells, including fibroblasts and osteoblasts during development, while PDGFRβ is primarily found on and associated with blood vessels. These expression patterns contribute to the tissue-specific responses elicited by PDGF signaling, with PDGFRα mediating broader proliferative effects in mesenchymal lineages and PDGFRβ supporting vascular stability.

Intracellular Signaling

Upon ligand-induced dimerization and activation, platelet-derived growth factor receptors (PDGFRs) undergo autophosphorylation on multiple intracellular residues, generating high-affinity docking sites for Src homology 2 (SH2) domain-containing adaptor and effector proteins. These phosphotyrosine (pY) motifs recruit key signaling molecules such as 3-kinase (PI3K), Cγ (PLCγ), and Src family kinases, initiating diverse downstream cascades that mediate cellular responses like proliferation, migration, and . The specific pY sites vary between PDGFRα and PDGFRβ isoforms; for instance, pY740 and pY751 on PDGFRβ bind the p85 regulatory subunit of PI3K, while pY1009 and pY1021 recruit PLCγ and Src, respectively. The recruited proteins activate several major intracellular pathways. The /extracellular signal-regulated kinase (MAPK/ERK) pathway, stimulated via Grb2-Sos-Ras activation often involving Src, promotes by driving transcription of genes like c-fos and cyclin D1. The PI3K/Akt pathway, triggered by PI3K lipid kinase activity, enhances cell survival and motility by phosphorylating targets such as Bad and glycogen synthase -3β (GSK-3β), inhibiting . Additionally, the /signal transducer and activator of transcription (JAK/STAT) pathway contributes to gene expression regulation; PDGF induces tyrosine phosphorylation of and via JAK2 and Src, leading to their dimerization, nuclear translocation, and activation of mitogenic genes like c-myc. This simplified sequence of receptor autophosphorylation on (Y) residues → pY-SH2 binding underscores the initiation of these pathways. PDGF signaling integrates with other pathways through crosstalk, amplifying or modulating responses. For example, PDGFRs interact with signaling via direct association or shared effectors like Src and FAK, enhancing ERK activation and in adhesive contexts. Similarly, overlap with pathways occurs through the shared JAK/STAT axis, where PDGF can potentiate STAT activation alongside cytokine receptors, influencing inflammatory and proliferative outcomes. Negative regulation ensures signaling fidelity and termination. Protein phosphatases (PTPs), such as PTP1B and TC-PTP, dephosphorylate PDGFR phosphotyrosines, attenuating activity and downstream effects; for instance, TC-PTP promotes receptor recycling and limits prolonged ERK signaling. Feedback loops further constrain pathways, including ERK-mediated inhibition of the Grb2-Sos complex to dampen Ras activation, and ubiquitin ligase Cbl-induced PDGFR ubiquitination leading to lysosomal degradation. These mechanisms prevent excessive signaling and maintain cellular .

Physiological Roles

Developmental Functions

Platelet-derived growth factor (PDGF) plays essential roles in embryonic development by regulating , proliferation, and differentiation through . During embryogenesis, PDGF ligands, particularly PDGF-A and PDGF-B, interact with their cognate receptors PDGFRα and PDGFRβ to orchestrate key morphogenetic processes, including vascular stabilization and organ formation. These functions are most prominent in mid-gestation stages, such as embryonic day 10.5 (E10.5) in mice, when PDGF expression peaks in specific tissues to guide patterning and tissue assembly. In vascular development, PDGF-B expressed by endothelial cells binds to PDGFRβ on pericyte progenitors, promoting their , proliferation, and investment around nascent endothelial tubes to stabilize blood vessels. This paracrine mechanism is critical for , particularly in the , where PDGF-B expression is strongest in angiogenic sprout tip cells around E10. This process ensures proper vessel maturation and prevents structural weaknesses. In PDGF-B mice, pericyte recruitment fails, leading to a deficiency in , endothelial , and the formation of lethal microaneurysms in organs like the and ; embryos exhibit dilated vessels and hemorrhages, resulting in perinatal lethality around E16–E19. PDGF-A contributes to by directing the migration and patterning of cells and supporting alveolar formation in the . In development, PDGF-A, produced by epithelia and , acts as a chemoattractant to guide cranial and cardiac cell via PDGFRα signaling, which regulates epithelial-mesenchymal transition and interactions, including and modulation. Although PDGF-A null mice do not show overt defects, PDGFRα knockouts result in cranial malformations, , and incomplete cardiac contribution leading to ventricular septal defects. In development, PDGF-A drives the proliferation and distal spreading of alveolar smooth muscle cell progenitors from the midline, essential for secondary septation and alveolarization; its absence causes an emphysema-like phenotype with enlarged airspaces due to failed myofibroblast recruitment. PDGF-A null mice also exhibit skeletal abnormalities, including rib fusion and sternal defects, highlighting its role in mesenchymal patterning. PDGF signaling coordinates with (FGF) pathways to refine patterning during . In chick and models, PDGF-A enhances mesodermal cell toward FGF4 gradients, regulating N-cadherin expression via PI3K to facilitate directed migration from the without altering initial mesoderm specification. This interaction ensures proper mediolateral patterning and intercalation of mesodermal cells, integrating proliferative cues from PDGF with differentiative signals from FGF.

Tissue Repair and Homeostasis

Platelet-derived growth factor (PDGF) is released from activated platelets and macrophages at sites of tissue injury, initiating key reparative processes in adult . Upon vascular damage, platelets degranulate to discharge PDGF isoforms, particularly PDGF-BB, which acts as a potent and chemoattractant for and cells. Macrophages, recruited to the injury site, further amplify this response by secreting PDGF-BB, stimulating fibroblast proliferation and the synthesis of (ECM) components such as and , thereby promoting formation and wound closure. In angiogenesis during tissue repair, PDGF-DD contributes to stabilizing and maturing nascent blood vessels within healing wounds. Expressed by and , PDGF-DD binds to PDGF receptor-β (PDGFRβ) on , recruiting to endothelial tubes and enhancing vascular integrity through ECM deposition and coverage, which prevents leakage and supports nutrient delivery to regenerating tissues. This maturation process is essential for transitioning from proliferative to remodeling phases of , ensuring functional vascular networks. Beyond injury response, PDGF contributes to tissue homeostasis by regulating fluid balance through PDGFRα signaling in fibroblasts. In steady-state conditions, PDGF ligands activate PDGFRα on fibroblasts, modulating cellular tension and ECM remodeling via phosphatidylinositol-3-kinase (PI3K) pathways, which maintain appropriate fluid pressure and prevent . This homeostatic function supports overall tissue and structural integrity in organs like the skin and lungs. Studies in animal models demonstrate PDGF's impact on wound repair efficiency; targeted PDGF-B overexpression via adenoviral delivery in diabetic mouse models enhances formation and neovascularization, leading to faster rates compared to controls. Hypoxic conditions in injured tissues further regulate PDGF expression through hypoxia-inducible factor-1α (HIF-1α), which transcriptionally upregulates PDGF genes to coordinate repair. Under low oxygen, stabilized HIF-1α binds to hypoxia response elements in PDGF promoters, particularly for PDGF-B, enhancing its production in macrophages and to drive and fibroblast activation during the proliferative phase of .

Clinical Applications

Therapeutic Uses

Becaplermin, a recombinant form of platelet-derived growth factor BB (PDGF-BB), was approved by the U.S. (FDA) in 1997 as a topical for the treatment of lower extremity diabetic neuropathic ulcers that extend into the or beyond and have an adequate blood supply. The mechanism involves stimulating and of cells critical for wound repair, such as fibroblasts, endothelial cells, and monocytes, thereby accelerating formation and epithelialization. In a combined analysis of four randomized, double-blind, -controlled phase III trials involving 478 patients with nonhealing diabetic foot ulcers, becaplermin (100 μg/g) applied daily increased the incidence of complete to 50% compared to 36% with (p=0.007) for ulcers ≤10 cm², with the time to complete healing reduced by approximately 30% (median 14.1 weeks vs. 20.1 weeks, p=0.01). In regenerative medicine, PDGF-BB has been incorporated into scaffolds for bone and periodontal tissue regeneration, particularly in dental applications. For instance, GEM 21S, an FDA-approved (2005) growth-factor enhanced matrix combining recombinant human PDGF-BB with beta-tricalcium phosphate, promotes bone fill, periodontal ligament regeneration, and cementum formation in intrabony periodontal defects and localized alveolar ridge augmentation around dental implants. Augment Bone Graft, approved by the FDA in 2015, incorporates rhPDGF-BB with beta-tricalcium phosphate for use in hindfoot and ankle fusion procedures as an alternative to autograft, supported by a randomized controlled trial showing non-inferior fusion rates (86.4% vs. 89.6% at 12 months). Clinical studies demonstrate that PDGF-BB enhances osteogenesis and vascularization in these matrices, leading to improved implant stability and bone volume compared to bone grafts alone, with bone fill rates up to 4.5 mm in periodontal defects after 6-12 months. Investigational combination therapies pairing PDGF with (VEGF) aim to enhance in ischemic conditions by promoting both endothelial cell (via VEGF) and pericyte recruitment for vessel maturation (via PDGF). Preclinical and early-phase human trials using vectors delivering PDGF-B and VEGF-A have shown prolonged neovascularization and improved in models of and myocardial ischemia, though no combined formulation is currently approved for clinical use. Delivery methods for therapeutic PDGF include topical formulations like the becaplermin gel for direct application and sustained-release matrices for orthopedic and dental sites, as well as investigational approaches using adenoviral or vectors to express PDGF isoforms locally in ischemic tissues. A phase II randomized, double-blind, -controlled trial in the late 1990s evaluated becaplermin for pressure ulcers, reporting higher healing rates (45% [14/31] complete closure at 16 weeks) versus (13% [4/31]), supporting its potential extension to other chronic wounds beyond diabetic ulcers, though not yet FDA-approved for venous leg ulcers.

Diagnostic and Prognostic Roles

Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) serve as valuable biomarkers in clinical diagnostics and prognostics, particularly in fibrotic and neoplastic conditions. In fibrosis, serum levels of PDGF isoforms, such as PDGF-AA and PDGF-BB, are elevated in systemic sclerosis (scleroderma), reflecting disease activity and fibroblast activation; for instance, bronchoalveolar lavage fluid from scleroderma patients shows significantly higher PDGF-AA and PDGF-BB concentrations compared to controls, correlating with pulmonary involvement. Similarly, in liver fibrosis associated with chronic hepatitis B, serum PDGF-BB levels increase with advancing fibrosis stages and can serve as a non-invasive marker for assessing disease progression. These elevations highlight PDGF's role in monitoring fibrotic burden without invasive procedures. In , (IHC) for PDGFR expression in tumor biopsies aids in grading and . High PDGFR-α and PDGFR-β protein expression is significantly associated with malignant in both adult and pediatric gliomas, with IHC revealing upregulated receptors in higher-grade tumors compared to low-grade ones, supporting its use in histopathological assessment. For prognosis, elevated PDGF-B or PDGFR-β in stroma correlates with increased risk and poorer outcomes; studies from large cohorts demonstrate that high stromal PDGFR-β expression, often driven by PDGF-B ligands, predicts biochemical recurrence and metastatic progression post-prostatectomy. Emerging liquid biopsy approaches leverage circulating PDGF isoforms for non-invasive monitoring of treatment response in cancer. Extracellular vesicles expressing PDGF-β have been identified as potential biomarkers in liquid biopsies from cancer patients, enabling serial assessment of disease dynamics and therapeutic efficacy without tissue sampling. Quantification of PDGF in plasma or serum typically employs enzyme-linked immunosorbent assay () kits, which provide sensitive and reproducible measurements of isoforms like PDGF-BB, facilitating their integration into routine clinical workflows for and cancer surveillance.

Pathological Implications

Involvement in Diseases

Dysregulated platelet-derived growth factor (PDGF) signaling contributes to the of various cancers through overexpression and autocrine stimulation. In , PDGF-BB forms an autocrine loop that drives tumor and survival by activating PDGF receptor beta (PDGFR-β), promoting the transformed of malignant cells. Similarly, in dermatofibrosarcoma protuberans, a fuses the COL1A1 gene with PDGFB, leading to ectopic production of PDGF-BB that stimulates autocrine and via PDGFR-β, thereby enhancing tumor growth and invasion. In fibrotic diseases, PDGF isoforms play a key role in activation and deposition. Specifically, PDGF-C is upregulated in models, where it activates PDGFR-α on s, inducing their differentiation into myofibroblasts and exacerbating fibrotic remodeling through and proliferation. In (IPF), PDGF levels in fluid and lung tissue are elevated, correlating with disease severity and hyperactivity. PDGF also promotes vascular pathology in atherosclerosis by stimulating smooth muscle cell proliferation within plaques. Endothelial cells, particularly under disturbed shear stress conditions, secrete PDGF-BB, which acts on PDGFR-β in vascular smooth muscle cells to induce migration, proliferation, and phenotypic modulation, contributing to intimal thickening and plaque instability. Mutations in the PDGF receptor gene PDGFRA underlie certain rare genetic disorders, notably gastrointestinal stromal tumors (GIST). Activating mutations in PDGFRA, occurring in approximately 5-10% of GIST cases, lead to ligand-independent receptor autophosphorylation and downstream signaling that drives uncontrolled proliferation of interstitial cells of Cajal, resulting in tumor formation predominantly in the .

Targeted Therapies

Targeted therapies for platelet-derived growth factor (PDGF) signaling primarily involve inhibitors that block PDGF receptors (PDGFRs), aiming to disrupt aberrant activation in diseases such as cancers and . inhibitors (TKIs) represent a cornerstone of these approaches, with (Gleevec) being the first approved TKI targeting PDGFRs. inhibits PDGFRα and PDGFRβ, in addition to other kinases like BCR-ABL and KIT, and was initially approved by the FDA in 2001 for chronic myeloid leukemia (CML) due to its activity against BCR-ABL. Its application expanded to gastrointestinal stromal tumors (GIST) in 2002, where it targets KIT and PDGFRα mutations driving oncogenesis. In PDGFRA-mutant GIST (excluding resistant D842V mutations), at 400 mg daily yields partial response rates of approximately 60-70% and clinical benefit in over 80% of patients, significantly improving compared to historical controls. For PDGFRA exon 18 mutations including D842V, which confer primary resistance to , (Ayvakit) was approved by the FDA in 2020, showing objective response rates of about 84% in clinical trials. Monoclonal antibodies targeting PDGFRs have also been developed, with olaratumab (Lartruvo) as a notable example. Olaratumab is a IgG1 that binds PDGFRα, preventing ligand-induced receptor dimerization and downstream signaling. It received accelerated FDA approval in 2016 for use in combination with in adults with advanced (STS) not amenable to surgery or radiation, based on phase II data showing improved overall survival (median 26.5 months vs. 14.7 months with doxorubicin alone). However, confirmatory phase III trials failed to replicate these benefits, leading to its voluntary withdrawal from the market by the manufacturer in 2019, with FDA concurrence in 2020. Other small molecule multi-kinase inhibitors, such as sunitinib (Sutent), incorporate PDGFR inhibition within broader anti-angiogenic profiles. Sunitinib potently inhibits PDGFRα and PDGFRβ, alongside VEGFRs and KIT, and was approved by the FDA in 2006 for advanced renal cell carcinoma (RCC) following cytokine-refractory disease, based on phase III data demonstrating a median progression-free survival of 11 months versus 5 months with interferon alfa. In metastatic RCC, where PDGF signaling contributes to tumor angiogenesis and stromal support, sunitinib's PDGFR blockade reduces vascular permeability and tumor growth, establishing it as a first-line option until newer immunotherapies supplanted it. Despite these advances, resistance to PDGF-targeted therapies poses significant challenges, often arising from pathway bypass mechanisms. For instance, activating in the PI3K/AKT/ axis, such as PIK3CA gain-of-function variants, can sustain cell survival and proliferation independently of PDGFR inhibition, as seen in resistant GIST and RCC models. These hyperactivate downstream effectors, circumventing TKI blockade and leading to disease progression, with preclinical studies highlighting the need for combination strategies targeting PI3K to restore sensitivity. Ongoing clinical efforts focus on refining anti-PDGF strategies for fibrotic conditions, where PDGF drives excessive deposition. has shown promise in early pilot studies for systemic sclerosis (SSc)-associated , with reports of lung function stabilization in over 50% of patients and a trend toward improvement in forced . More recently, phase II trials of novel anti-PDGF agents, including PDGFR-specific antibodies and small molecules, are investigating efficacy in SSc , aiming to halt progression; for example, a multicenter phase II study evaluates PDGFR modulation in early diffuse SSc, with interim data suggesting improved modified Rodnan skin scores. These trials underscore the potential of targeted PDGF inhibition to address unmet needs in antifibrotic therapy.

Current Research

Emerging Findings

Recent studies utilizing single-cell sequencing (scRNA-seq) have highlighted the heterogeneity in PDGF-driven gliomas, revealing distinct subpopulations of cells that contribute to tumor progression and resistance. For instance, in , scRNA-seq analyses have identified PDGF-driven cell states that exhibit varying levels of proliferative and invasive potential, underscoring the role of PDGF signaling in shaping intratumor diversity. Investigations into the role of PDGF in COVID-19-associated lung have demonstrated elevated PDGF levels in patients with severe outcomes, particularly in the development of post-infection pulmonary sequelae. Data from 2021-2023 cohorts indicate that high serum PDGF concentrations, alongside other profibrotic markers like TGF-β, are associated with activation and persistent fibrotic changes in the lungs, contributing to long-term respiratory impairment in survivors. These findings suggest PDGF as a key mediator in the transition from acute to chronic following SARS-CoV-2 infection. Non-canonical functions of PDGF in immune modulation have emerged, particularly its influence on T-cell activation. Recent 2024 papers demonstrate that PDGF-DD isoform binding to NKp44 on plasmacytoid dendritic cells costimulates TLR9 signaling, indirectly enhancing T-cell proinflammatory responses and production in antiviral immunity. This reveals PDGF's broader role beyond activity, extending to of adaptive immune dynamics in inflammatory contexts.

Future Directions

In precision medicine, genotyping for mutations in PDGF receptors offers substantial potential for tailoring inhibitor therapies to individual cancer patients. Activating in PDGFRA, such as the exon 18 D842V variant found in 5-10% of gastrointestinal stromal tumors, enable selection of targeted inhibitors like , which effectively address resistance by binding the inactive receptor conformation. Similarly, rearrangements in myeloid neoplasms with respond to following confirmation, improving remission rates in responsive subtypes. Preclinical investigations in the 2020s have highlighted nanoparticle-based delivery systems as a promising avenue for administering PDGF to promote healing. nanoparticles integrated into electrospun fibers provide sustained PDGF release, enhancing migration and proliferation in vitro while accelerating closure in diabetic models. nanospheres co-encapsulating PDGF and VEGF genes further demonstrate improved , formation, and deposition in preclinical diabetic ulcers, underscoring the potential for controlled, localized delivery to overcome degradation challenges in impaired healing environments. The role of PDGF in neurodegeneration remains an area of significant unresolved inquiry, with emerging links to illustrating its complex, context-dependent effects. PDGF-BB exerts neuroprotective actions by safeguarding hippocampal neurons against and energy deprivation through antioxidant pathway activation and mitochondrial preservation, yet reduced PDGFB expression in AD-affected brains correlates with degeneration and blood-brain barrier breakdown, potentially exacerbating amyloid-beta accumulation and vascular dysfunction. These contradictory findings—protective in some models but contributory to pathology in others—necessitate further studies to delineate PDGF's mechanistic contributions to Alzheimer's progression and evaluate its therapeutic modulation. Advancements in are facilitating sophisticated modeling of PDGF signaling networks to accelerate . Hybrid frameworks, incorporating and algorithms like K DEEP, have screened vast compound libraries to identify novel PDGFR inhibitors for non-small cell , predicting binding affinities through molecular fingerprint analysis and dynamics simulations that capture pathway perturbations. By simulating interactions such as hydrogen bonding in the PDGFRA domain, these AI-driven approaches enable precise targeting of oncogenic signaling, reducing experimental timelines and enhancing hit rates for inhibitors. Gene editing of PDGF-related loci in heritable diseases, exemplified by gain-of-function PDGFRB mutations driving familial infantile myofibromatosis, presents profound ethical challenges. CRISPR-Cas9-based germline corrections could mitigate multigenerational transmission of such variants, which cause aggressive vascular tumors, but raise risks of off-target mutations, genetic mosaicism, and unintended phenotypic alterations across generations. Key concerns include obtaining for edited embryos, preventing non-therapeutic enhancements that evoke , and navigating international prohibitions on heritable editing until safety benchmarks are met.

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