PDGF E. W. Raines* Department of Pathology, University of Washington, Health Science Building J507 Box 357470, Seattle, WA 98195-7470, USA * corresponding author tel: 206-685-7441, fax: 206-685-3018, e-mail:
[email protected] DOI: 10.1006/rwcy.2000.08003.
SUMMARY Different dimeric forms of platelet-derived growth factor (PDGF) are key regulators of connective tissue cells in embryogenesis and in the pathogenesis of a number of diseases. During development, PDGF-B/ PDGF receptor signaling controls mesangial cell development in kidney glomeruli (LeveÂen et al., 1994; Lindahl et al., 1998) and the recruitment of vascular smooth muscle cells (SMCs) and pericytes in developing blood vessels (Lindahl et al., 1997a; Crosby et al., 1998; HellstroÈm et al., 1999), while PDGF-A/ PDGF receptor signaling is critical for the recruitment of alveolar SMCs and alveogenesis (BostroÈm et al., 1996; Lindahl et al., 1997b) and for O-2A progenitor cell expansion in developing rat optic nerve, which gives rise to oligodendrocytes and type 2 astrocytes (Noble et al., 1988; Raff et al., 1988). The newly defined PDGF-C also targets mesenchymal cells, and may be particularly important in the development of the kidney mesenchyme and physiological and pathophysiological remodeling of the cardiac interstitium (Li et al., 2000). The potent effects of PDGF on mesenchymal cells in development, particularly SMCs, is recapitulated in wound healing and in multiple inflammatory diseases, where PDGF appears to be important for the recruitment of connective tissue cells and matrix deposition in the fibrotic response.
BACKGROUND
Discovery PDGF was originally discovered because it was the principal source of growth factor activity in whole blood serum for mesenchymal cells that was missing
in cell-free, plasma-derived serum (Kohler and Lipton, 1974; Ross et al., 1974). Although the possibility that platelets might serve as a source of growth factor activity was postulated by Balk (1971), it was not until it was shown that platelets could restore all of the growth factor activity missing from plasma that the significance of the platelet as a source of this activity became clear. These observations led to the purification and characterization of multiple molecular forms of PDGF from human platelets (Antoniades, 1981; Heldin et al., 1981a) and plateletrich plasma (Deuel et al., 1981; Raines and Ross, 1982).
Alternative names Because of the near identity of p28sis, the transforming product of simian sarcoma virus, with the B chain of PDGF (Robbins et al., 1983), PDGF is sometimes referred to as c-sis.
Structure PDGF is a family of homo- and heterodimers of two distinct cationic polypeptide chains (PDGF A chain and B chain), whose interchain and intrachain disulfide bonds (Giese et al., 1987; Hannink and Donoghue, 1988; OÈstman et al., 1992; Haniu et al., 1993) are responsible for its tight knot-like structure (Oefner et al., 1992). Recently, a third PDGF family member (PDGF-C) has been identified that only forms homodimers (Li et al., 2000).
Main activities and pathophysiological roles The ability of PDGF to stimulate mesenchymal migration, proliferation, survival, and multiple
756 E. W. Raines specific cellular functions, including extracellular matrix deposition, led to the hypothesis that it may be important for multiple fibroproliferative responses in disease states (Ross et al., 1974; Westermark and Wasteson, 1976; Ross et al., 1986). The deletion of either the PDGF A or B chain or either of the two PDGF receptors is embryonic lethal (LeveÂen et al., 1994; Soriano, 1994, 1997; BostroÈm et al., 1996). An analysis of the null embryos has demonstrated an important role for PDGF in mesenchymal cell recruitment in the kidney, blood vessels, lungs, and central nervous system. A unique role for PDGF-C is indicated from analysis of kidneys lacking the PDGF receptor that shows selective loss of mesenchymal cells adjacent to sites of PDGF-C mRNA expression that are not found in kidneys from animals lacking PDGF-A or both PDGF-A and PDGF-B (Li et al., 2000). Similarly, in wound repair and in multiple diseases, the PDGF recruitment of connective tissue cells contributes to the fibroproliferative response and to disease pathogenesis (Betsholtz and Raines, 1997).
GENE AND GENE REGULATION
Accession numbers PDGF A chain: NM 002607 (short); X03795 (long) PDGF B chain: Z81010 PDGF C chain: W21436 (EST)
Chromosome location The genes for the PDGF A and B chains are located on chromosomes 7 (Dalla Favera et al., 1982; Swan et al., 1982; Betsholtz et al., 1986) and 22 (Bonthron et al., 1988; Stenman et al., 1988) respectively.
Regulatory sites and corresponding transcription factors PDGF A Chain An unusual feature of the PDGF A chain mRNA is the presence of a long 50 untranslated region (UTR) containing three AUG triplets upstream of the initiator codon (Bonthron et al., 1988; Rorsman et al., 1988). The first two AUG are in close proximity in the same reading frame and are closely followed by a stop codon. It would be predicted that the complicated leader sequence might impair translation.
A highly GC-rich region, containing three contiguous specificity protein 1 (SP-1)-binding sites between bp ÿ150 and ÿ33, and overlapping early growth response factor 1 (Egr-1)-binding sites, are responsible for over 80% of the promoter activity (Lin et al., 1992; Wang and Deuel, 1992; Kaetzel et al., 1993). In smooth muscle cells, SP-1 and SP-3 bind to the promoter and independently or additively activate it (Silverman et al., 1997). Egr-1 is induced by a number of stimuli, including shear stress (Khachigian et al., 1997), and can compete with SP-1 to activate the promoter further (Silverman et al., 1997). Strainresponsive regions between ÿ92 bp and ÿ41 bp of the promoter have also been identified (Wilson et al., 1998), and strain only induced binding with an Egr-1 probe but not with an SP-1 probe. In contrast, methylation of the promoter appears to repress its activity (Lin et al., 1993). Regions involved in the repression of the PDGF A chain include those between ÿ1029 and ÿ883 and between ÿ1800 and ÿ1029 in the renal epithelial cell line BSC-1 (Kaetzel et al., 1994; Liu et al., 1996), and the first intron in HeLa cells (Wang et al., 1994; Nobuyoshi et al., 1997). The Wilms' tumor suppressor gene product binds to several sites in the PDGF A chain promoter and functions as a repressor (Wang et al., 1992; Lee et al., 1997). Recently, a cloned DNA binding factor, GC factor 2 (GCF2), has been shown to repress the human PDGF A chain promoter by competing with SP-1 and Egr-1 for interaction with the promoter (Khachigian et al., 1999). GCF2 is induced on the mechanical injury of cells in culture and after balloon injury of the rat carotid artery. Data are consistent with GCF2 acting as an endogenous transcriptional repressor. PDGF B Chain A minimal promoter for the PDGF B chain extending only 42 bp upstream of the TATA signal is as efficient as 4 kb upstream of the TATA in driving expression in unstimulated K562 cells (Pech et al., 1989). Laminar shear stress induces PDGF B chain expression, and a 6 bp core element has been defined as a shear stress response element (Resnick et al., 1993). Using electrophoretic mobility shift assays and in vitro DNAse I footprinting, it has been demonstrated that NFB p50±p65 heterodimers bind to the PDGF B chain shear stress response element in endothelial cells (Khachigian et al., 1995). Egr-1 has also been shown to interact with a novel element in the proximal PDGF B chain promoter and to compete for SP-1 binding after injury of endothelial cells (Khachigian et al., 1995). Elements associated with thrombin-induced PDGF B chain
PDGF 757 transcription in endothelial cells (Scarpati and DiCorleto, 1996) and the TPA induction of K562 cells (Pech et al., 1989) have been defined. In osteosarcoma cells, SP-1 and SP-3 have been identified as primary transcriptional mediators (Liang et al., 1996). SP-1 and SP-3 have also been shown to be elevated in newborn rat smooth muscle cells that constitutively express the PDGF B chain (Rafty and Khachigian, 1998). The long 50 UTR of the PDGF B chain strongly inhibits its synthesis (Horvath et al., 1995). Inaccessibility of the promoter, as a result of cell type-specific DNase-I hypersensitivity sites, appears to contribute to inhibition of the expression of the endogenous gene (Franklin et al., 1991; Dirks et al., 1993). Transactivating factors have also been implicated in the negative regulation of the PDGF B chain in somatic cell hybrids between PDGF B chain-expressing melanoma cells and hamster fibroblasts (LeveÂen et al., 1993). Furthermore, the long 50 UTR of the PDGF B chain has translational modulating activity due to its differentiation-activated internal ribosomal entry site, and the elements required for differentiation-sensing ability have been mapped to a 630 nucleotide fragment within the central portion of the 50 UTR (Bernstein et al., 1997; Sella et al., 1999). Transcripts lacking the translational inhibitory effect of exon 1 appear to be initiated within the first alternative exon (Fen and Daniel, 1991; Dirks et al., 1995). The expression of a 2.6 kb PDGF B chain mRNA lacking the inhibitory 50 untranslated sequence was found to correlate with increased PDGF B chain immunoreactivity during rat brain development (Sasahara et al., 1998).
Cells and tissues that express the gene PDGF may be expressed by a multiplicity of normal cells and tissues (Table 1). Although PDGF A, B, and C chains are expressed constitutively in the brain (Sasahara et al., 1991; Yeh et al., 1991; Li et al., 2000), their expression in normal cells is highly regulated (Raines et al., 1990; Raines and Ross, 1993). For a number of cell types, placing isolated cells in culture is sufficient to induce PDGF mRNA expression (Raines and Ross, 1993). Conversely, culture conditions that more closely mimic those in vivo decrease PDGF expression (Raines and Ross, 1993). PDGF expression in vivo is increased following injury and in a number of disease states (Table 2), including tumors of multiple cell origin (Table 3).
PROTEIN
Accession numbers GenPept: A chain: NP 002598 (short); CAA27421 (long) B chain: CAV02635 Crystal structure: PDGF-BB ± MMDB, 1872; PDB, 1PDG
Sequence The amino acid sequences for the PDGF A and B chains are shown in Figure 1a. The sequences have been aligned to allow a comparison of the amino acid sequences of the two chains, and demonstrate the significant homology between the two chains (51% over the 109 amino acids of the PDGF B chain). The newly cloned PDGF-C shares 27±35% homology with PDGF-A and PDGF-B over exons 4 through 7 (Li et al., 2000). Phylogenetic analysis of PDGF-C and domains of PDGF-A and -B and the related family of vascular endothelial growth factor (VEGF) shows that PDGF-C is closer to VEGFs than to PDGFs (Li et al., 2000).
Description of protein PDGF is a family of homo- and heterodimers of two distinct but homologous genes, PDGF A chain and B chain and homodimers of PDGF-C (see Figure 1). The processed forms of PDGF A, B, and C chain vary from 125, 108, and up to 184 amino acids in length, respectively. An analysis of PDGF purified from lysed human platelets, using chain-specific monoclonal antibodies, suggests that approximately 70% is PDGF-AB, the remainder being PDGF-AA and PDGF-BB (Hammacher et al., 1988a; Hart et al., 1990). Other cells that express both chains of PDGF also contain all three PDGF isoforms (Hammacher et al., 1988b; OÈstman et al., 1988), suggesting that dimer assembly may be a random process. The maintenance of the tertiary structure by intrachain disulfide bonds is required for biological activity (Heldin et al., 1979; Raines and Ross, 1982; Antoniades and Williams, 1983; Giese et al., 1987; Kenney et al., 1994). Both A and B chains are synthesized as precursor proteins (Figure 1b) and undergo processing at the Ntermini (A and B chain) and C-terminus (B chain). Two forms of the PDGF A chain are synthesized from alternatively spliced forms, with and without the
758 E. W. Raines Table 1 Normal cells and tissues that express PDGF Cell
Protein
mRNA
Reference
PDGF-A
PDGF-B
Connective tissue cells Fibroblasts Dermal, human
+
+
ÿ
Raines et al., 1989
Foreskin, human
+
+
ÿ
Paulsson et al., 1987
+
+
+
Gnessi et al., 1992, 1995
+
+
+
Marra et al., 1994
+
+
+
Shultz et al., 1988
+
+
ÿ
Sejersen et al., 1986
+
+
+
Gnessi et al., 1995
Aortic, carotid, femoral, human
+
+
ÿ
Libby et al., 1988
Aortic, adult rat
+
+
ÿ
Sejersen et al., 1986
Aortic, newborn rat
+
+
+
Seifert et al., 1984
Aortic, bovine
+
+
+
DiCorleto and Bowen-Pope, 1983
Iliac, human
+
+
+
Sitaras et al., 1987
Renal microvascular, human
+
+
+
Daniel et al., 1986
Umbilical vein, human
+
+
+
Collins et al., 1987a, 1987b
Venous, human
+
+
+
Limanni et al., 1988
+
+
+
Kim et al., 1999
Leydig cells Leydig cells, rat Liver fat-storing cells, human Mesangial cells Mesangial cells, human Muscle cells Myoblasts, rat skeletal Peritubular myoid cells Developing and postnatal, rat Vascular smooth muscle
Endothelial/epithelial cells Endothelial cells
Epithelial cells Corneal, human Iris pigment, human
+
+
Kociok et al., 1998
Keratinocytes, human
+
+
+
Ansel et al., 1993
Kidney, African green monkey (BSC-1)
+
ÿ
+
Kartha et al., 1988
Pancreatic islet cells, human
+
+
Retinal pigment, rat
+
+
+
Campochiaro et al., 1989; Kociok et al., 1998
Sertoli cells, developing rat
+
+
+
Gnessi et al., 1995
Ebert et al., 1998
Mesothelial cells Pleural, human
+
Gerwin et al., 1987
Hematopoietic cells Erythrocytes Erythroid cells, mouse
+ +
Keutzer and Sytkowski, 1995 +
+
Bidwell et al., 1995
PDGF 759 Table 1 (Continued ) Cell
Protein
mRNA PDGF-A
Reference PDGF-B
Monocyte/macrophages Alveolar, human
+
Blood monocytes, human
ÿ
Activated monocytes, human
+
+
+
Sariban and Kufe, 1988; Ross et al., 1990
+
+
+
Hart et al., 1990; Wickenhauser et al., 1995
+
+
+
Noble et al., 1988; Raff et al., 1988; Richardson et al., 1988
+
+
+
Sasahara et al., 1991
Platelets/megakaryocytes
+
Shimokado et al., 1985 Ross et al., 1990
Nervous tissue cells Type I astrocytes, rat Neurons Primate Mouse Retinal ganglion, rat Schwann cells, rat
+
Yeh et al., 1991
+
+
Fruttiger et al., 1996
+
+
+
Hardy et al., 1992
+
+
Barrett and Benditt, 1988
Tissues Aorta Human Bone, bovine
+
Hauschka et al., 1988
Brain Caudate-putamen, primate
+
Sasahara et al., 1991
Cerebellum, primate
+
+
+
Sasahara et al., 1991; Yeh et al., 1991
Cortex, primate
+
+
+
Sasahara et al., 1991; Yeh et al., 1991
Hippocampus, primate
+
+
+
Sasahara et al., 1991; Yeh et al., 1991
Optic nerve, rat
+
+
Sciatic nerve, rat
+
+
+
Hardy et al., 1992
Carotid endarterectomy, human
+
+
Barrett and Benditt, 1988
Cornea, human
+
+
Kim et al., 1999
Mudhar et al., 1993
Embryo Unfertilized oocyte, mouse Blastocyst, mouse
+
Xenopus Epidermis
+
Rappolee et al., 1988
+
Rappolee et al., 1988
+
Mercola et al., 1988
+
+
+
+
+
Ansel et al., 1993
Kidney Human Developing, mouse
+
Young et al., 1990; Alpers et al., 1995 +
Seifert et al., 1998
Liver, human
+
Young et al., 1990
Lung, human
+
Young et al., 1990
+
Young et al., 1990
Muscle Muscle, human
760 E. W. Raines Table 1 (Continued ) Cell
Protein
mRNA PDGF-A
Developing muscle, rat Pancreas, human
+
Reference PDGF-B
+
Jin et al., 1990
+
Ebert et al., 1998
Placenta First trimester, human
+
Second trimester, human
+
Third trimester, human
+
+
Retina, rat
+
+
Hyaloid rat
+
+
Goustin et al., 1985
+
Taylor and Williams, 1988 Gurski et al., 1999
Eye Mudhar et al., 1993 +
Mudhar et al., 1993
Thyroid, human
+
Young et al., 1990
Teeth, developing mouse
+
Chai et al., 1998
+
Young et al., 1990
Testis Testis, human Developing and postnatal, rat
+
+
+
Gnessi et al., 1995
Uterus, human
+
Boehm et al., 1990
Uterus, human gravid
+
Mendoza et al., 1990
Uterus
Table 2 PDGF ligand and receptor expression are increased in human disease Disease
PDGF chains A
Atherosclerosis
PDGF receptors B
+
Libby et al., 1988 +
+ Restenosis Cirrhosis of the liver
Ross et al., 1990
+
Wilcox et al., 1988
+ +
Reference
+
+
+
Rubin et al., 1988
+
Tanizawa et al., 1996
+
Pinzani et al., 1996
Diabetes
Guillausseau et al., 1989
Glomerulonephritis
+ +
Nakashima et al., 1992
+
Matsuda et al., 1997
+
Taniguchi et al., 1996 +
Inflammatory bowel disease +
+
+
+
FellstroÈm et al., 1989
+
Gesualdo et al., 1994
+
Alexander et al., 1995 Beck and Podolsky, 1999
PDGF 761 Table 2 (Continued ) Disease
PDGF chains
PDGF receptors
+
+
Reference
A
B
Myelofibrosis
+
+
Proliferative retinal diseases
+
+
Idiopathic
+
+
Nagaoka et al., 1990
Histiocytosis X
+
+
Uebelhoer et al., 1995
Katoh et al., 1990 Robbins et al., 1994
Pulmonary fibrosis
Rheumatoid arthritis
+
Reuterdahl et al., 1991
Scleroderma
+
Klareskog et al., 1990
+ Cardiac transplant rejection Renal transplant rejection
+ +
Gay et al., 1989 +
Zhao et al., 1995
+
Shaddy et al., 1996
+
Alpers et al., 1996
+
+
Floege et al., 1998 +
FellstroÈm et al., 1989
Table 3 Expression of PDGF by tumors and tumor cells Cell
Protein
mRNA
Reference
PDGF-A
PDGF-B
Connective tissue tumors Fibrosarcoma, human
+
+
+
Taniuchi et al., 1997
Kaposi's sarcoma, human
+
+
+
Sturzl et al., 1992
Osteosarcoma, human (U-2OS)
+
+
+
NisteÂr et al., 1988
+
+
Collins et al., 1987a
+
+
Raines et al., 1990
(U-1810) Epithelial cell tumors (carcinomas) Bladder, human (T24) Breast, human
+
+
Coltrera et al., 1995
+
+
+
Bronzert et al., 1987
Colon, human (COLO-201, COLO-205)
+
+
+
Sariban et al., 1988
Esophageal, human
+
+
+
Yoshida et al., 1993
Gastric, human
+
+
Chung and Antoniades, 1992
(KATO III)
+
+
Sariban et al., 1988
(MCF-7, MDA-MB-231)
Liver, human (Hep G2) Lung, human (CALU-1) (U-1810) Mammary, human (MDA-MB-468) (BT-20, MCF-7, ZR-75-1)
+
+
+
Bowen-Pope, 1984b
+
+
+
Raines et al., 1990
+
+
+
Sariban et al., 1988
+
+
+
Betsholtz et al., 1987
+
ÿ
+
Peres et al., 1987
+
+
+
Sariban et al., 1988
762 E. W. Raines Table 3 (Continued ) Cell
Protein
mRNA
Reference
PDGF-A
PDGF-B
+
+
+
Peres et al., 1987; Sariban et al., 1988
+
+
+
Barnhill et al., 1996
(WM-115)
+
+
+
Westermark et al., 1986
(WM-239A, WM-266-4)
+
+
ÿ
Westermark et al., 1986
+
+
+
Gerwin et al., 1987
+
+
Gerwin et al., 1987
+
ÿ
Gerwin et al., 1987
(MDA-MB-157, T47D, HBL-100) Melanoma, human
Mesothelial, human (HUT-28) (DND, JMN, MT-1, MT-3, VMAT-1) (HUT-290) Ovarian, human (ARM, DUN, MAC, SAM)
+
+
+
Sariban et al., 1988
Pancreatic, human (PANC-I and HPAF)
+
+
+
Ebert et al., 1995
Pituitary, human
+
+
+
Leon et al., 1994
Prostate, human adenocarcinomas
+
+
ÿ
Fudge et al., 1994
Erythroleukemic cells, human (HEL, K562)
+
+
+
Papayannopoulou et al., 1987
Pre-B leukemic cells, human (SMS-SB)
+
+
Hematopoietic cell tumors Tsai et al., 1994
Promyelocytic, human (HL-60)
+
Promonocytic, human (U937)
+
Alitalo et al., 1987
Promonocytic, human (THP-1)
+
Sariban and Kufe, 1988
T cells transformed with HTLV-I and II
+
Pantazis et al., 1986; Alitalo et al., 1987
+
+
+
Pantazis et al., 1987; Goustin et al., 1990
+
+
ÿ
Fraizer et al., 1987
(human stem cell line Tera-2 clone 13)
+
+
ÿ
Weima et al., 1988
(mouse endoderm-like F9)
+
+
ÿ
Wang and Stiles, 1993
+
Fahrer et al., 1989
+
+
Maxwell et al., 1990
+
+
Black et al., 1996
Mixed cell tumors Nephroblastoma, human Wilms' tumor Teratocarcinoma
Muscle cell tumors Rhabdomyosarcoma, human
+
Nervous tissue tumors Astrocytomas, human
+
Ependymomas, human Glioblastoma, human
+
ÿ
+
Gillaspy et al., 1992
(A172)
+
ÿ
+
Vassbotn et al., 1994
(patient with LiFraumeni syndrome)
+
+
ÿ
Guha et al., 1995
+
NisteÂr et al., 1988
Gliomas, human Medulloblastomas, human
+
ÿ
Black et al., 1996
Meningiomas, human
+
+
Black et al., 1994
+
Van Zoelen et al., 1985
+
Di Rocco et al., 1998
Neuroblastomas (mouse 2A) Oligodendrogliomas, human
+ +
PDGF 763 Figure 1 PDGF A- and B-chain: Amino acid sequences, protein processing, and different dimeric isoforms (a) The amino acid sequences of the PDGF A- and B-chain deduced from the nucleotide sequence of cloned cDNA are shown and aligned for comparison of homology between the two chains. The alignment is adapted from Bonthron et al. (1988) and dots represent gaps introduced to improve alignment. The N- and C-terminals cleavage sites are shown by arrows (A-chain, green; B-chain, blue). Boxes indicate exons and each exon is numbered above. Astrisks indicate matching residues. The two alternatively spliced sequences for the PDGF A-chain are shown for exons 6 and 7 (AL, the long from of the A-chain, yellow; AS, the short form of the A-chain, red). Figure adapted from Raines et al. (1990). (b) The processing of the PDGF A- and Bchains is illustrated with the signal sequence indicated by the zig-zag line, the pro-sequence by a line, and the mature protein is boxed (A-chain, green; and alternatively spliced sequences as indicated in (a)). Positions with consensus N-linked glycosylation sites have been indicated with a branched structure. (c) The six different dimeric combination of PDGF A- and B-chains are shown. (Full colour figure can be viewed online.)
exon 6-encoded sequence (Betsholtz et al., 1986; Collins et al., 1987a). In both the A and the B chain, exon 1 encodes the signal sequence, while exons 2 and 3 encode precursor sequences removed during processing, exons 4 and 5 encode the mature protein, exon 6 is alternatively spliced in the A chain and may be removed during maturation of the B chain, and exon 7 is primarily a noncoding sequence (Johnsson
et al., 1984; Bonthron et al., 1988; OÈstman et al., 1988, 1992; Rorsman et al., 1988). PDGF-C has a twodomain structure not previously observed in this family of growth factors: (1) an N-terminal CUB domain first found in complement subcomponents C1r/C1s, urchin EGF-like protein and bone morphogenetic protein 1, which may be involved in protein±protein and protein±carbohydrate interactions; (2) a C-terminal
764 E. W. Raines PDGF/VEGF-homology domain. The two domains are connected by a hinge region (Li et al., 2000). PDGF-C is synthesized and secreted as a latent growth factor, requiring proteolytic removal of the Nterminal CUB domain for receptor binding and activation. Alternative splicing of the PDGF A chain and processing of the C-terminus of the PDGF B chain regulate the inclusion or exclusion of the highly basic sequence encoded by exon 6 whose inclusion may promote intracellular retention (LaRochelle et al., 1991) and matrix association (Pollock and Richardson, 1992; Raines and Ross, 1992; Kelly et al., 1993; Andersson et al., 1994). If the A and B chains are made by a single cell and both alternatively spliced forms of the A chain are transcribed, six dimeric combinations are possible (Figure 1c). The recent expression of the full-length PDGF B chain and a truncated form lacking exon 6 in genetically engineered human keratinocytes that were grafted as epithelial sheets onto athymic mice demonstrated that the different binding properties control the spatial organization of cellular events in regenerating mesenchymal tissues (Eming et al., 1999).
Discussion of crystal structure The crystal structure of human recombinant PDGFBB (Oefner et al., 1992) demonstrates that the polypeptide chain is folded into two highly twisted, antiparallel pairs of strands. Each of the chains creates three loops, two (loops 1 and 3) extending in one direction and one (loop 2) in the opposite direction, which upon dimerization forms a complex of all three loops contributed to by different chains. Mutation of the loop 2 region of the PDGF A and B chain significantly decreases binding to both the PDGF and receptors (Andersson et al., 1995), while specific amino acid residues in loop 1 of the PDGF B chain appear to be important primarily for binding to the PDGF receptor; the Lys161 in loop 3 is involved in binding to the PDGF receptor (Kreysing et al., 1996; Schilling et al., 1998), and the three cationic amino acid residues in loop 3 also contribute to heparin binding activity (Schilling et al., 1998). The tight cystine-knot topology of PDGF chains is shared with not only the highly homologous VEGF family (Muller et al., 1997), but also two other growth factors, TGF and nerve growth factor (Murray-Rust et al., 1993). It has been suggested that the structural motif of disulfide bonds and hydrogen-bonded strands found in these growth factors with divergent amino acid sequences serves as a framework for the
elaboration of loops that contain the specificity for receptor interaction. In spite of the diversity in the sequence of PDGF-C with that of PDGF-A and -B, which includes the different spacing of the cysteine residues in the central, most highly conserved region of this domain with an insertion of three amino acids that occurs close to the loop 2 region thought to be involved in receptor binding, PDGF-C dimers bind to the PDGF receptor with an almost identical affinity to that of PDGF-AA or PDGF-BB (Li et al., 2000).
Important homologies PDGF A and B chains share 60% amino acid homology, with a perfect conservation of the eight cysteine residues. Members of the VEGF family share a similar spacing between cysteine residues (Keck et al., 1989; Tischer et al., 1989; Conn et al., 1990), although their target cells and activities are distinct. The eight conserved cysteine residues are also found in PDGF-C, but their spacing is different with the insertion of three amino acids between cysteines 3 and 4 (Li et al., 2000). An additional four cysteine residues are present in PDGF-C and are located between cysteines 3 and 4, 5 and 6, 6, and 7, and beyond the eighth conserved cysteine (Li et al., 2000). The overall sequence homology of PDGF-C with PDGF-A and -B is only 27 to 35%. The unique N-terminal CUB domain only found in PDGF-C shares 27±37% identity with the prototypic CUB domains in C1r/C1s and bone morphogenic protein 1 (Li et al., 2000).
Posttranslational modifications An analysis of processing of the v-sis gene product (Hannink and Donoghue, 1986) and the PDGF B chain (Kaetzel et al., 1996) demonstrates that mutants lacking the N-linked glycosylation site are properly folded, are secreted and are biologically active. However, in the case of the PDGF B chain, the absence of the N-glycosylation site decreases the accumulation of the intracellular species (Kaetzel et al., 1996).
CELLULAR SOURCES AND TISSUE EXPRESSION
Cellular sources that produce Although the PDGF B chain can be expressed in a number of normal cells in culture (see Table 1), its constitutive expression in normal cells and tissues
PDGF 765 appears to be primarily limited to extensive areas of the central nervous system (Sasahara et al., 1991), in particular neurons, and to epithelial cells (Raines and Ross, 1993). The PDGF A chain is more ubiquitously expressed in normal cells as it can be found in smooth muscle cells and fibroblasts throughout the body, in thyroid, muscle, kidney, liver, heart, thymus, and testis as well as the central nervous system (Table 1). The recently cloned PDGF C chain has a unique expression profile that includes the highest level of expression in heart, liver, kidney, pancreas and ovary; smaller amounts of mRNAs in most other tissues, including placenta, skeletal muscle and prostate; and undetectable levels of mRNAs in spleen, colon and peripheral blood leukocytes (Li et al., 2000).
Eliciting and inhibitory stimuli, including exogenous and endogenous modulators Coincident with the tight regulation of PDGF expression in normal cells, a number of eliciting stimuli associated with cellular injury have been identified, as have inhibitory agents that are capable of locally limitating the induction of PDGF (Table 4). The cellular response to PDGF appears to be highly dependent on the local environment independent of the PDGF receptor level. For example, smooth muscle cells (SMCs) cultured on plastic or monomeric type I collagen that normally proliferate in response to PDGF are arrested in G1 and fail to respond to PDGF if plated on polymerized collagen (Koyama et al., 1996). In contrast, fibronectin fibril formation appears to be required for SMC proliferation (Mercurius and Morla, 1998). Thus, the extracellular matrix surrounding the cell can regulate its response to PDGF. We have hypothesized that the matrix surrounding SMCs in the normal media of the vascular wall may be nonpermissive to SMC proliferation (Raines et al., 2000). Polarized secretion, as observed in endothelial cells, which is almost exclusively restricted to the basal compartment (Zerwes and Risau, 1987), can limit the access of surrounding cells to released PDGF. PDGF can also be inhibited by endogenous inhibitors that bind PDGF and inhibit its interaction with its receptors. Plasma binding proteins for PDGF (Raines et al., 1984) include 2-macroglobulin (Raines et al., 1984; Huang et al., 1984), which binds PDGFAB and -BB but not PDGF-AA (Bonner and Osornio-Vargas, 1995). PDGF preferentially binds to native 2-macroglobulin (LaMarre et al., 1991), but the oxidation of 2-macroglobulin, which could
occur in atherosclerotic lesions, decreases the binding of PDGF-BB (Wu et al., 1998) and could thus impair its inhibitory activity. Soluble receptors for PDGF have also been identified in human plasma (Tiesman and Hart, 1993), but little is known about conditions or enzymes responsible for receptor shedding. Other matrix proteins known to bind PDGF include SPARC (Raines et al., 1992), heparin sulfate proteoglycans (Raines and Ross, 1992; Feyzi et al., 1997; Gohring et al., 1998; Lustig et al., 1999), NG2 chondroitin sulfate proteoglycan (Goretzki et al., 1999) and thrombospondin (Hogg et al., 1997). A novel binding protein expressed in a rat neural retina cell line that co-purified with PDGF-AA has been shown to enhance the mitogenic activity of PDGF-AA but decrease the activity of PDGF-BB (Fischer and Schubert, 1996). The specificity of binding and inhibition (Table 5) suggests that more endogenous inhibitors exist for the binding and inhibition of PDGF-AB and -BB than for PDGF-AA. These endogenous binding proteins may help to explain the very rapid clearance (a half-life of less than 2 minutes) of PDGF from the circulation (Bowen-Pope et al., 1984a). Less is known about modulation of the newly identified PDGF-C. However, the fact that it is secreted as an inactive precursor that requires proteolytic removal of the N-terminal CUB domain provides a new level of regulation (Li et al., 2000). Analysis of endogenous and transgenic PDGF-C in heart tissue demonstrates that the protein is processed in vivo. The presence or absence of necessary activating enzymes, therefore, will be critical for induction of PDGF-C activity.
RECEPTOR UTILIZATION As detailed in the PDGF receptor chapter and illustrated in Figure 2, the different dimeric forms of PDGF bind and transmit specific signals via two different receptor subunits that can also form heteroand homodimers with distinct binding patterns (Hart et al., 1988; Heldin et al., 1988; Seifert et al., 1989; Heldin and Westermark, 1999; Li et al., 2000). The capacity of the homo- and heterodimers of PDGF to induce multiple cell functions depends on both the PDGF dimer present and the relative number of the two different PDGF receptor subunits on the responding cells (Seifert et al., 1989; Ferns et al., 1990). PDGF-AA is able to bind only PDGF receptor homodimers, PDGF-AB binds PDGF receptor homodimers and PDGF and receptor heterodimers, while PDGF-BB is able to bind all receptor combinations (Figure 2). The newly identified
766 E. W. Raines Table 4 Eliciting and inhibiting stimuli Stimulus
Target cell/tissue
PDGF induction
Reference
A chain
B chain
ÿ
+
Handa et al., 1998
+
Kirstein et al., 1990
Eliciters AGEs
Epithelial cells Monocytes
-Adrenergic agonists
SMCs
+
ÿ
Majesky et al., 1990b
Blood pressure
Vascular SMCs
+
+
Negoro et al., 1995
IL-1
SMCs and fibroblasts
+
ÿ
Raines et al., 1989; Kawaguchi et al., 1999
TGF
Mammary epithelium
+
ÿ
Bronzert et al., 1990
TGF
SMCs, fibroblasts,
+
ÿ
Battegay et al., 1990
TNF , TGF
Mesangial cells
Cytokines
Osteoclasts +
Astrocytes TNF
Fibroblasts
+
Silver et al., 1989 +
Silberstein et al., 1996
ÿ
Paulsson et al., 1989
+
Keutzer and Sytkowski, 1995
+
Gray et al., 1995
Erythropoietin
Erythroid progenitors
Estrogen
Uterus and vagina
+
Mesangial cells
+
HB-EGF
Endothelial cells
+
PDGF-AA and BB
Bone cell cultures
+
Rydziel et al., 1994
+
Paulsson et al., 1987
Growth factors PDGF, EGF, bFGF, TGF
PDGF Hypoxia
Brain, neonatal rat
Lipopolysaccharide
Endothelial cells, human pulmonary
PDGF
Fibroblasts
+
Osteoblasts
+
Pressure
Mesangial cells
ÿ
Shear stress
Endothelial cells
Step and impulse
ÿ
Silver et al., 1989 ÿ
Gay and Winkles, 1990
+
Ohno et al., 1999
+
Albelda et al., 1989
+
Paulsson et al., 1987 Rydziel et al., 1994
+
Kato et al., 1999
+
Resnick et al., 1993; Khachigian et al., 1995
+
Bao et al., 1999 Wilson et al., 1998
Strain
SMCs
+
Thrombin
Mesangial cells
+
SMCs
+
ACE inhibitors
Endothelial cells
+
+
Yamaguchi et al., 1994
+
+
Wong et al., 1997
Calcium channel blockers
Endothelial cells
+
+
Yamaguchi et al., 1994
Carbon monoxide
Endothelial cells
+
Morita and Kourembanas, 1995
Glucocorticoid
SMCs
+
Nakano et al., 1993
Oxidized LDL
Monocytes
+
Malden et al., 1991
+
Shultz et al., 1989 Okazaki et al., 1992
Inhibitors
+
PDGF 767 Table 5 Binding proteins for different dimeric forms of PDGF Binding protein
PDGF-AA long
PDGF-AA short
PDGF-BB
PDGF-AB
Inhibition or enhancement
2-Macroglobulin
ND
ÿ
+
+
ÿ
Heparan sulfate proteoglycan
+
ÿ
+
ND
ÿ
NG2 proteoglycan
ND
+
ÿ
ND
ÿ
PDGF-associated protein (PAP)
ND
+
PAP
ÿ +
ND
+
SPARC
ÿ
ÿ
+
+
ÿ
Thrombospondin
ND
ND
+
ND
+
Figure 2 The binding of PDGF to its receptor subunit pairs depends on the chain composition of the PDGF dimer. Two types of PDGF receptor subunits exist: PDGF receptor that can bind PDGF A- and Bchains, and PDGF -receptor which only binds PDGF B-chain. Thus, PDGF-BB can bind to all three subunit pairs of PDGF receptors ± receptors, -receptors, and -receptors; PDGF-AB can bind two subunit receptor pair ± -receptors and receptors; while PDGF-AA is only able to bind only to -receptors.
PDGF-CC only binds PDGF receptor homodimers (Li et al., 2000).
IN VITRO ACTIVITIES
In Vitro findings The in vitro activities of PDGF have been extensively characterized, especially for mesenchymal cells, whose stimulation served as the basis for its purification.
PDGF is a potent stimulant of the proliferation of mesenchymal cells and stem cells of multiple lineages, but a more limited stimulant of endothelial and epithelial cells. It is also a potent stimulant of the proliferation of vascular smooth muscle cells (Ross et al., 1974), kidney mesangial cells (Shultz et al., 1988), dermal fibroblasts (Heldin et al., 1981b), glial cells (Heldin et al., 1981b), testicular peritubular myoid cells (Gnessi et al., 1992), muscle cells (Jin et al., 1991), osteoblasts (Centrella et al., 1991), and chondrocytes (Raines et al., 1990; Kieswetter et al., 1997). In many cases, such as osteoblasts and chondrocytes, the PDGF stimulation of proliferation prevents differentiated function (Hock and Canalis, 1994; Kieswetter et al., 1997). Within the nervous system, PDGF released by type 1 astrocytes stimulates O-2A progenitor cells in developing rat optic nerve, which gives rise to oligodendrocytes and type 2 astrocytes (Noble et al., 1988; Raff et al., 1988). Schwann cells also proliferate in response to PDGF in the presence of forskolin or other agents that raise the intracellular cyclic AMP level (Davis and Stroobant, 1990). Some of the growth-promoting activity of PDGF appears to be indirect and mediated through the induction of other growth stimulants specific for the cell types (Raines et al., 1990). Examples include the PDGF enhancement of erythropoietic progenitor cell proliferation (Dainiak et al., 1983; Delwiche et al., 1985), the promotion of T cell proliferation (Daynes et al., 1991), and the stimulation of primitive hematopoietic precursors (Yan et al., 1993). Although PDGF has been reported to be angiogenic in vivo (Risau et al., 1992), it appears primarily to stimulate angiogenesis by locally stimulating other potent angiogenic stimulants, such as VEGF (D. Wang et al., 1999) and matrix, such as type I collagen (Sato et al., 1993). However, PDGF-BB has been shown to induce functional vascular anastomoses in vivo (Brown et al., 1995), regardless of a direct or indirect mechanism.
768 E. W. Raines The first report of the PDGF stimulation of an epithelial tissue was its stimulation of growth of the lens in an organ culture system (Brewitt and Clark, 1988). A proliferative and migratory response to PDGF-BB has been demonstrated for rabbit gastric epithelial cells (Watanabe et al., 1996).
products. The induction of other cytokines following PDGF stimulation, including its own induction (Paulsson et al., 1987), may serve as a means to amplify its proliferative effects.
PDGF as a Survival Factor
The chemotaxis of arterial smooth muscle cells in a Boyden chamber assay with collagen-coated filters is stimulated by all dimeric forms of PDGF and is dependent upon the relative expression levels of the different PDGF receptors (Ferns et al., 1990). PDGF also stimulates the migration of fibroblasts (Seppa et al., 1982), human keratinocytes (Andresen and Ehlers, 1998), human retinal pigment epithelial cells (Campochiaro and Glaser, 1985), and neuroepithelial stem cells (Forsberg-Nilsson et al., 1998). PDGF as a potential chemoattractant for neutrophils and monocytes (Deuel et al., 1982; Williams et al., 1983) is more controversial (Graves et al., 1989), which may be because of a requirement for activation of the monocytes and neutrophils by cytokines or lymphocytes to induce PDGF responsiveness (Shure et al., 1992).
Since PDGF promotes the proliferation of connective tissue-synthesizing cells, the ability of PDGF to modify the matrix was examined shortly after its purification. PDGF composed of a mixture of the different isoforms was shown both to promote matrix synthesis via the stimulation of collagen and thrombospondin synthesis, and to promote matrix breakdown via the promotion of collagenase activity (Raines et al., 1990). It has subsequently been shown that a number of other extracellular matrix constituents are regulated by PDGF, including the stimulation of hyaluronan synthesis (P. Heldin et al., 1989), of versican chondroitin sulfate proteoglycans (SchoÈnherr et al., 1991), of the small chondroitin sulfate/dermatan sulfate proteoglycans biglycan and decorin (SchoÈnherr et al., 1993), of lysyl oxidase, which may modulate matrix organization (Green et al., 1995), of the alternative splicing of fibronectin, which alters its cell-binding properties (McKay et al., 1994), of alternatively spliced forms of tenascin (LaFleur et al., 1994), and of both plasminogen activators (Pfeilschifter et al., 1992; Kenagy and Clowes, 1995) and the receptor for urokinase-type plasminogen activator receptor (Reuning and Bang, 1992). It is likely that the induction of these matrix constituents may be critical for many of the effects of PDGF, as has been demonstrated for smooth muscle cell migration and proliferation, which is dependent on urokinase and tissue-type plasminogen activator (Herbert et al., 1997).
Induction of `Early Genes'
PDGF Modulation of Specific Cellular Functions
The PDGF stimulation of responsive cells regulates the expression of a discrete group of low-abundance and labile gene products (Rollins and Stiles, 1988). At least three of these immediate early genes ± c-fos, cmyc, and Egr-1 ± appear to act as intracellular mediators of the PDGF mitogenic response (Kelly et al., 1983; Cochran et al., 1984; Greenberg and Ziff, 1984; Santiago et al., 1999). In the case of neuroepithelial cells from the developing cortex, the immediate early gene response is sufficient to specify the neuronal fate (Williams et al., 1997). JE and KC are two other `early genes' induced by PDGF (Rollins et al., 1988) that encode monocyte chemotactic protein 1 (Rollins, 1991) and melanocyte growth factor (Oquendo et al., 1989) respectively, which are proinflammatory gene
The effects of PDGF on specific cellular functions are dependent on the cell type. In oligodendrocytes, PDGF relieves the astrocyte inhibition of myelin basic protein mRNA transport into cell processes and cytoplasmic channels that infiltrate the myelin sheath, important for myelination (Amur-Umarjee et al., 1997); in 3T3-L1 adipocytes, PDGF promotes glucose uptake by translocation of the glucose transporter (L. Wang et al., 1999); cationic amino acid transporter gene expression is stimulated in smooth muscle cells and supports proliferation (Durante et al., 1996); PDGF stimulates mesangial cell ion channels that would promote sustained extracellular calcium entry in human skin fibroblasts (Ling et al., 1995), and modulates junctional cell-to-cell communication
During development, cell turnover is modulated by both proliferation and apoptosis. In the developing rat optic nerve, about 50% of the oligodendrocytes normally die as a result of competition for a limited number of survival signals, one of which is PDGF (Barres et al., 1992). PDGF-AA and -BB are also survival factors for neurons from ventral mesencephalon from rat and human embryos (Nikkhah et al., 1993), developing Schwann cells (Meier et al., 1999), and a rat hippocampal cell line (Kwon, 1997). PDGF Stimulates Directed Cellular Migration
Modification of Cell Matrix Constituents by PDGF
PDGF 769 (Maldonado et al., 1988; Hossain et al., 1999); both PDGF-AA and -BB induce the low-density lipoprotein receptor gene (Rechtoris and Mazzone, 1995); PDGF inhibits human natural killer cell activity (Gersuk et al., 1991); and it enhances the expression of -amino-e-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor 1 in endocortical neurons through the Src family kinase Fyn (Narisawa-Saito et al., 1999); in blood monocytes, PDGF-BB induces the expression of the tissue factor that may promote inflammation (Ernofsson and Siegbahn, 1996); plasminogen activator inhibitor 1 stimulation by PDGF in smooth muscle cells may regulate the fibrinolytic system (Reilly and McFall, 1991); and in human trabecular cells, PDGF facilitates phagocytosis (Tamura and Iwamoto, 1989).
Regulatory molecules: Inhibitors and enhancers As discussed above, the response of cells expressing PDGF receptors is highly dependent on the extracellular matrix environment and on the level of endogenous binding proteins for PDGF (see Table 5), which bind and inhibit PDGF binding to responsive cells. Some of the binding proteins, such as the PDGF-associated protein (Fischer and Schubert, 1996) and thrombospondin (Hogg et al., 1997), do not interfere with receptor binding and appear to enhance PDGF activity.
Bioassays used The principal bioassays used to evaluate PDGF activity are the PDGF radioreceptor assay (Bowen-Pope and Ross, 1985) and the stimulation of connective tissue proliferation in the presence and absence of PDGF neutralizing antibodies, as, for example, reported for brain-derived PDGF (Sasahara et al., 1991).
IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS
Normal physiological roles
development (reviewed in Betsholtz, 1995; Ataliotis and Mercola, 1997; Lindahl and Betsholtz, 1998; Heldin and Westermark, 1999; Li et al., 2000). A common theme observed in both mammalian development as well as in Xenopus (Jones et al., 1993; Ghil and Chung, 1999) and sea urchin (Ramachandran et al., 1997) development is that ectodermally produced PDGF may act on mesoderm during gastrulation. Mesenchymal cells throughout the embryo and within particular developing organs express PDGF receptors, while PDGF A, B, and C chains are often secreted by adjacent epithelial cells or endothelial cells. Pericytes and mesangial cells failed to develop in PDGF B chain-deficient embryos (Lindahl et al., 1997a; LeveÂen et al., 1994), whereas alveolar smooth muscle cells failed to develop in PDGF A chaindeficient embryos (BostroÈm et al., 1996; Lindahl et al., 1999). PDGF B chain also acts locally to contribute to the development of the labyrinthine layer of the fetal placenta and the formation of a proper nutrient± waste exchange system during fetal development (Ohlsson et al., 1999). A reduction in number of both pericytes and trophoblasts is observed in embryos deficient in either PDGF B chain or the PDGF receptor. Although PDGF-CC shares the same receptor with PDGF-AA, it appears to have a distinct expression profile and, thus, different roles (Li et al., 2000). This was predicted from PDGF receptor-null animals that show certain defects, such as cleft face and spina bifida, that are not seen in homozygous deletions of the genes for PDGF-A, PDGF-B, or both. Mouse embryos lacking PDGF receptor show an extensive loss of the cortical mesenchyme adjacent to sites of PDGF-C-expressing cells in early aggregates of metanephric mesenchyme undergoing epithelial conversion in the kidney (Li et al., 2000). Thus, it has been proposed that PDGF-C has an essential function in the development of the kidney mesenchyme. Patterns of PDGF ligand and receptor expression in the developing palate (Qiu and Ferguson, 1995), kidney (Alpers et al., 1992, 1995; Seifert et al., 1998), teeth (Chai et al., 1998), testis (Gnessi et al., 1995), myoblasts (Jin et al., 1990), retina (Mudhar et al., 1993; Frutigger et al., 1996), lens (Potts et al., 1994), rat optic nerve (Richardson et al., 1988; Barres et al., 1992), and spinal cord (Pringle and Richardson, 1993; Hall et al., 1996) are consistent with a role for PDGF in embryogenesis via both autocrine and paracrine signaling.
In the Developing Embryo
Nervous System
A large number of studies have demonstrated distinct roles for PDGF A, B, and C chain during
The importance of PDGF in the proliferation and migration of mesenchymal cells of the brain, glial
770 E. W. Raines cells, served as one of the bases for its purification (Westermark and Wasteson, 1976). However, its potential as a broad modulator of the nervous system was not suspected until a survey of normal tissues demonstrated a very significant expression of the PDGF B chain in neurons, principal dendrites, some axons, and probable terminals throughout the brain, as well as in the dorsal horn of the spinal cord and the posterior pituitary (Sasahara et al., 1991). Similarly, the expression of PDGF A chain mRNA is observed to have a similar distribution in adults (Sasahara et al., 1991; Yeh et al., 1991). These observations have led to a detailed examination of the responses of specific cells within the nervous system to PDGF, both in vitro and in vivo, and have led to the realization that PDGF is a central neurotrophic factor (Valenzuela et al., 1997). Although the significance of its actions are not totally understood, ligand-gated ion channels, both type A aminobutyric acid (GABAA) and N-methyl-D-aspartate (NMDA) receptors on neurons, are modulated by PDGF (Valenzuela et al., 1995, 1996) and may regulate synaptic plasticity in the brain (Valenzuela et al., 1997). More recently, PDGF has also been shown to increase the number of -amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (Narisawa-Saito et al., 1999), which may also contribute to the regulation of neuronal plasticity. PDGF has also been implicated in the protection of neurons. The administration of PDGF-BB prevents spinal motor neuron death in neonatal rats following sciatic nerve resection (Iwasaki et al., 1997) and delays neuronal death in CA1 pyramidal neurons after forebrain ischemia (Iihara et al., 1997; Kawabe et al., 1997). This is in agreement with the ability of PDGF-BB to enhance neuron survival following the intraocular transplantation of E14 ventral mesencephalon to sympathetically denervated host eyes (Giacobini et al., 1993), to reduce the loss of dopaminergic neurons in cultures from rat and human embryonic ventral mesencephalon (Nikkhah et al., 1993), to increase the survival of GABAergic neurons in a primary culture of newborn rat cerebellum (Smits et al., 1991), and to stimulate the neuronal cell survival factor, brain-derived neurotrophic factor, in a rat hippocampal stem cell line (Kwon, 1997). A potential role for PDGF in the modulation of neuronal energy metabolism has been suggested by the ability of PDGF to induce phosphorylation of the delta subunit of the F1F0 ATPase in cultured mouse cortical neurons (Zhang et al., 1995). Another role for PDGF in the nervous system was implied by our observations that PDGF inhibits the feeding response in the coelenterate Hydra (Hanai et al., 1987), one of
the earliest animals known to have a simple nerve net. The ability of PDGF to alter the feeding response has been confirmed in mammals by the intracerebroventricular injection of PDGF (Plata-SalamaÂn, 1988; Sasaki et al., 1991). In mammals, it appears that regulation of the feeding response by PDGF may be specific to particular phases. Normal Wound Repair Normal wound healing requires the concerted actions of a number of cell types. The earliest cells that appear in wounds are leukocytes, principally neutrophils together with monocytes, which become the dominant cell within a day or two following wounding. Subsequently, the ingress and proliferation of capillaries, fibroblasts, and smooth muscle cells ultimately leads to wound resolution (Ross, 1968). In addition to stimulating the migration and proliferation of particularly fibroblasts into the wound site, PDGF can modulate local gene expression (Rollins and Stiles, 1988; Raines et al., 1990), including that of cellular matrix constituents (Raines et al., 1990) and coagulation factors (Ernofsson and Siegbahn, 1996; Edelberg et al., 1998), and can regulate interstitial fluid pressure by altering tension on the extracellular matrix structures of fibroblasts and other connective tissue cells (Rodt et al., 1996; Heuchel et al., 1999). PDGF can be made by all of the cell types involved in wound repair, with the exception of the neutrophils, and the expression of PDGF depends on the local stimulants. Although circulating monocytes express a low or undetectable level of PDGF (Ross et al., 1990), infiltrating macrophages express PDGFBB/AB (Reuterdahl et al., 1993). Epithelial cells are also a major source of PDGF (see Table 1) and may thus be a significant source of PDGF following wounding of the epidermis (Ansel et al., 1993). PDGF expression is also observed in peripheral nerve fibers in wounds (Reuterdahl et al., 1993). Numerous studies have demonstrated the presence of PDGF in wound fluid in partial thickness wounds (Vogt et al., 1998), following mastectomy (Dvonch et al., 1992), during fracture repair (Andrew et al., 1995; Fujii et al., 1999), in tear fluid following photorefractive keratectomy (Vesaluoma et al., 1997), and in blisters of partial skin thickness burns (Ono et al., 1995). It has also been noted that, in addition to the presence of PDGF-BB and -AB, a markedly upregulated level of the long form of PDGF-AA, which preferentially binds the extracellular matrix, is observed in acute, surgically created wounds (Pierce et al., 1995). Furthermore, a reduced expression of PDGF and its receptors has been noted during impaired wound healing (Pierce et al., 1995; Beer et al., 1997).
PDGF 771 The expression of PDGF during the repair of injury is not limited to external wounds as it is also observed following arterial injury (Majesky et al., 1990a), periodontal wound healing (Lynch et al., 1991), bone fracture (Andrew et al., 1995; Fujii et al., 1999), nerve injury (Mekada et al., 1998; Ohno et al., 1999), kidney injury (Iida et al., 1991), and hypoxic lung injury (Katayose et al., 1993). Because of the critical problem of defective wound repair in patients who are bedridden for long periods of time, or who may have other chronic diseases, such as diabetes, that interfere with the healing process, several investigators have examined the effects of PDGF on granulation tissue formation in models of impaired wound healing (Grotendorst et al., 1985; Greenhalgh et al., 1990; Pierce et al., 1991, 1995; Liechty et al., 1999). PDGF significantly augments the time-dependent influx of inflammatory cells and fibroblasts, and accelerates provisional extracellular matrix deposition and subsequent collagen formation. In a tracheal wounding model, administration of PDGF-BB in a collagen±fibrin composite accelerated wound repair (Koempel et al., 1998). Although most studies utilized recombinant PDGF-BB (which binds and activates all forms of the PDGF receptor), the overexpression of PDGF-AA in genetically modified human keratinocytes has also been shown to enhance the performance of a skin graft (Eming et al., 1995, 1998). A comparison of the behavior of wild-type and null PDGF receptor cells within individual chimeric mice has revealed that the PDGF B chain is important for fibroblast and endothelial cell recruitment into sponge implants (Crosby et al., 1999). PDGF as a Possible Physiologic Mediator of Smooth Muscle Cell Function Changes in PDGF A chain expression in both vascular smooth muscle (Majesky et al., 1990b) and uterine smooth muscle (Boehm et al., 1990; Mendoza et al., 1990; Gray et al., 1995) associated with changes in their function suggest that PDGF may be a physiologic mediator of these functions (Raines and Ross, 1993). In the rat aorta, -adrenergic stimulation dose-dependently stimulates PDGF A chain gene expression (Majesky et al., 1990b). The induction of PDGF A chain was specific to 1adrenergic receptors as angiotensin II and endothelin, despite an increase in blood pressure, had little or no effect on the PDGF A chain level. Adrenergic stimulation of the PDGF A chain was coincident with increases in growth-related genes, but not DNA synthesis, which were associated with the trophic effects of sympathetic nerves and catecholamines on arterial smooth muscle cell mass and protein synthesis.
In a one-kidney, one-clip hypertensive rat model of nonrenin-dependent hypertension, PDGF A chain expression correlates with blood pressure and increased wall area (Dobrian et al., 1999). High blood pressure in spontaneously hypertensive rats (SHRs) is also associated with an increased level of the PDGF A chain (Negoro et al., 1995), and the administration of an antisense oligodeoxynucleotide to the PDGF A chain in SHRs did not alter the systolic blood pressure but markedly reduced the incorporation of [H3]thymidine into aortic DNA and suppressed elevated DNA content (Fukuda et al., 1997a). Interestingly, the long form of the PDGF A chain has been shown to be elevated in SHRs (Fukuda et al., 1997b). A comparison of human myometrium from normal uteri and gestational uteri demonstrated a 10- to 15fold increase in PDGF A chain expression at term and was associated with uterine expansion (Mendoza et al., 1990). An analysis of cell-specific RNA expression revealed that estrogen treatment decreases the level of PDGF and its receptors in both the uterus and vagina of the mouse (Gray et al., 1995). PDGF is also expressed in smooth muscle cell-like Leydig cells in the testis, it stimulates proliferation and matrix production (Gnessi et al., 1993), and its secretion is dose-dependently increased by the trophic hormone human chorionic gonadotropin (Gnessi et al., 1992). Thus, the hormonal regulation of uterine and testicular PDGF may mediate smooth muscle cell function. Other Possible Vascular Regulation by PDGF Although PDGF significantly modulates the functions of all smooth muscle cells and pericytes, as well as of some endothelial cells, PDGF does not appear to be absolutely required for particularly large vessel formation as a normal vascular network is observed in knockouts of both PDGF ligands and their receptors (LeveÂen et al., 1994; Soriano, 1994, 1997; BostroÈm et al., 1996). However, the PDGF B chain is particularly critical for the recruitment of vascular SMCs and pericytes, as shown by an analysis of PDGF B chain and PDGF receptor-null mice (Lindahl et al., 1997a; HellstroÈm et al., 1999), and PDGF receptor-null cells in mouse chimeras (Crosby et al., 1998). Although a role in adult animals has not been tested, it has been proposed that the PDGF B chain may play a similarly important role in these, for example in the venous wall that has only a rudimentary SMC coating before birth (HellstroÈm et al., 1999). The PDGF B chain is important for endothelial cell recruitment into sponge implants, as recently demonstrated by a comparison of the behavior of wild-type and null PDGF receptor cells within individual chimeric mice (Crosby et al., 1999).
772 E. W. Raines The role of PDGF in the regulation of vascular tone is less clear. In strips of rat aorta in vitro, a mixture of PDGF isoforms from platelets induces dose-dependent contraction (Berk et al., 1986). In contrast, rat intracerebral arterioles isolated from brain parenchyma did not respond to any of the dimeric forms of PDGF (Bassett et al., 1988), suggesting vascular bed-specific responses that may be dependent on PDGF receptor expression. PDGF-BB has also been reported to stimulate the nitric oxidemediated relaxation of rat aortic rings (Cunningham et al., 1992; Takase et al., 1999), which is consistent with data in which only PDGF-BB infusion into anesthetized rats lowered blood pressure (Ikeda et al., 1997). These differences are likely to reflect complex interactions between the endothelium and SMCs that may vary in different vascular beds. PDGF receptor expression on endothelium appears to be limited to capillary endothelial cells (Bar et al., 1989; Smits et al., 1989; Beitz et al., 1991; P. Heldin et al., 1991), and local PDGF expression adjacent to capillaries may control their function. Endothelial cells of different vascular beds synthesize discrete gene products associated with organ-specific tasks (Sawdey and Loskutoff, 1991; Weiler-Guettler et al., 1996; Aird et al., 1997). In the mouse heart, the myocyte modulation of PDGF expression by microvascular endothelial cells regulates the expression of hemostatic and angiogenic gene products, including von Willebrand factor, VEGF and its receptor, flk-1 (Edelberg et al., 1998). The localized expression of PDGF in brain, heart, and muscle, by astrocytes, cardiac myocytes, and skeletal myocytes respectively, also regulates endothelial nitric oxide synthase (Guillot et al., 1999). Thus, the actions of PDGF on genes involved in the regulation of angiogenesis and vascular tone may help to explain the variability of its purported actions in these two processes. Potential Role of PDGF in the Expansion of Stem Cell Populations During development, PDGF appears to play a major role in the expansion of certain stem cell populations, such as O2-A progenitor cells (Raff et al., 1988). Similarly in adults, PDGF may be important for the expansion of adult O-2A progenitor cells (Wolswijk and Noble, 1992) and of a pool of multipotent cell precursors that resides within the cerebral cortex (Marmur et al., 1998). PDGF also enhances the proliferation of myoblasts (Jin et al., 1991; YablonkaReuveni and Seifert, 1993) and may be important in the transition of adult satellite cells to proliferating myoblasts (Yablonka-Reuveni, 1995). This possibility could be tested in mice created from chimeric
blastocysts composed of a mixture of wild-type and PDGF receptor-null cells, which have demonstrated an 8-fold reduction in the participation of PDGF receptor-null cells in all muscle lineages (Crosby et al., 1998). PDGF may also influence circulating stem cell populations. Primitive multipotent hematopoietic precursors (pre-CFC multi) are stimulated by PDGF (Yan et al., 1993), as are erythroid precursors (Dainiak et al., 1983; Delwiche et al., 1985), both via indirect mechanisms in which they stimulate cytokine secretion from other cells. PDGF also stimulates megakaryocyte precursor growth (Yang et al., 1995), the precursors of platelets. Although a direct link to precursor growth has not been demonstrated, early B lineage precursor cells express PDGF receptors (Tsai et al., 1994; Trink et al., 1995) and may thus contribute to early B progenitor expansion.
Species differences The PDGF molecules appear to be highly conserved. An analysis of Xenopus laevis genomic DNA using human PDGF A and B chain probes demonstrated homologous species with 73% identity over the A chain coding region, including evidence for both the long and short forms of the A chain, and 53% and 65% sequence identity in the 50 and 30 UTRs respectively (Mercola et al., 1988). Phylogenetic analyses of clotted whole blood have demonstrated that PDGFBB is the predominant isoform in sera from mouse, rat, pig, cow, sheep, dog, and chicken, but not primates (Bowen-Pope et al., 1989), and that blood from all chordates contains PDGF while sera from tunicates to the arthropod line of development were negative (Singh et al., 1982). However, functional homologs of PDGF and its receptor appear to be present in even more primitive animals as the protozoan Tetrahymena responds chemotactically to PDGF and the small freshwater coelenterates Hydra release a PDGF homolog on wounding that inhibits their feeding response and is blocked by an antibody to human PDGF (Hanai et al., 1987; Raines et al., 1990). PDGF protein has also been detected in invertebrate and vertebrate immunocytes (Franchini et al., 1996).
Knockout mouse phenotypes A deletion of either the PDGF A or B chain is embryonic lethal (LeveÂen et al., 1994; BostroÈm et al., 1996). The phenotype of the knockout embryos has pointed to the particular importance of the PDGF B chain for the development of kidney glomeruli
PDGF 773 (LeveÂen et al., 1994; Lindahl et al., 1998) and suggests that although the mesangial cell lineage is independent of the PDGF B chain, it is required for the recruitment of PDGFR -positive progenitors surrounding the developing glomerular afferent and efferent arterioles during angiogenic formation of the glomerular capillary tuft (Lindahl et al., 1998, 1999). PDGF B chain knockouts have also demonstrated the importance of PDGF B chain in the recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation (Lindahl et al., 1997a; HellstroÈm et al., 1999). The recruitment of alveolar smooth muscle cells, important for elastin fibre formation, is also a major defect in PDGF A chain-deficient embryos (BostroÈm et al., 1996; Lindahl et al., 1997b). Expression patterns and mutant phenotypes suggest that epidermal cell PDGF A chain expression is important for dermal mesenchymal proliferation and may contribute to the formation of dermal papillae, mesenchymal sheaths and dermal fibroblasts (Karlsson et al., 1999). As predicted from the dependence of oligodendrocyte development on astrocyte production of the PDGF A chain (Noble et al., 1988; Raff et al., 1988), embryos lacking the PDGF A chain have defective oligodendrocyte development and severe hypomyelination (Fruttiger et al., 1999). Many of the phenotypes in PDGF A and B chain knockouts are also observed in PDGF receptor knockouts (Soriano, 1994, 1997). The presence of additional defects in PDGF receptornull embryos as compared with homozygous deletions of the genes for PDGF-A, PDGF-B, or both, appears to be explained by the identification of the PDGF-C gene (Li et al., 2000).
Transgenic overexpression As would be predicted from the potent activities of PDGF on mesenchymal cells and knockout studies of both PDGF chains, the overexpression of PDGF particularly stimulates connective tissue cell accumulation. Overexpression of the PDGF B chain in hematopoietic cells in mice induces a lethal myeloproliferative syndrome (Yan et al., 1994); overexpression of the PDGF A chain under the control of the lens-specific A crystallin promoter result in cataracts and retinal astrocyte hyperplasia (Reneker and Overbeek, 1996a, 1996b); keratinocyte-produced PDGF-AA promotes epidermal±dermal interactions and promotes the growth and vascularization of dermal tissue (Eming et al., 1995), as well as improving graft performance (Eming et al., 1998); while PDGF-BB accelerates gastric epithelial cell restoration (Watanabe et al., 1996) and corrects ischemic
impaired wound healing (Liechty et al., 1999). Transgenic overexpression of PDGF-C in mice using the -myosin heavy chain promoter induced strong proliferation of myocardial interstitial cells, such as cardiac fibroblasts (Li et al., 2000).
Interactions with cytokine network The PDGF stimulation of responsive cells induces the expression of a number of cytokines as part of the `early gene' response, as detailed above. A number of cytokines can also regulate the expression of PDGF (see Table 4 and above).
Endogenous inhibitors and enhancers As discussed above, the response of cells expressing PDGF receptors is highly dependent upon the extracellular matrix environment and on the level of endogenous binding proteins for PDGF (see Table 5), which bind and inhibit PDGF binding to responsive cells. Some of the binding proteins, such as the PDGF-associated protein (Fischer and Schubert, 1996) and thrombospondin (Hogg et al., 1997), do not interfere with receptor binding and appear to enhance PDGF activity.
PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY
Normal levels and effects As we have already discussed, although PDGF may be expressed by a multiplicity of normal cells and tissues (see Table 1), its expression in normal cells is highly regulated. PDGF has a number of effects in developing embryos, in the nervous system, in normal wound repair, as a physiological mediator of SMC function, in vascular regulation, and in the expansion of stem cell populations as discussed above.
Role in experiments of nature and disease states The expression of PDGF and its receptors is increased in a number of disease states (see Table 2), including neoplasias of multiple cell origins (see
774 E. W. Raines Table 3). Whereas normal tissue repair results in simple scar formation, prolonged inflammation may result in the excessive accumulation of connective tissue cells and extensive matrix deposition, with potentially pathological consequences. As discussed below, for several of the disease states listed in Table 2 above, a common feature of those diseases associated with an increased expression of PDGF and its receptors is the recruitment and stimulation of the local SMC population. Atherosclerosis and Restenosis Atherosclerosis remains the leading cause of death despite changes in lifestyle and effective pharmacologic regimens to lower cholesterol level, one of the principal risk factors for atherosclerosis (Breslow, 1997). A common feature that atherosclerosis shares with a number of other disease processes is that it is an inflammatory disease (Ross, 1999). Although a number of growth factors and cytokines in addition to PDGF are increased in the lesions of atherosclerosis (Raines and Ross, 1996), recent evidence in a nonhuman primate model of restenosis (Giese et al., 1999) provides support for previous studies in other animal models (Raines and Ross, 1993) that the blockade of PDGF receptors may reduce neointimal lesion formation. PDGF expression is increased in circulating mononuclear cells of hypercholesterolemic patients (Billett et al., 1996), and PDGF B chain expression is observed in macrophages in lesions at all stages of atherosclerosis (Ross et al., 1990). In advanced lesions in nonhuman primates, PDGF A and B chain expression is observed in both macrophages and SMCs (Evanko et al., 1998). Expression of the PDGF receptor is increased following angioplasty in human (Tanizawa et al., 1996) and nonhuman primate (Giese et al., 1999), and blockade of the PDGF receptor inhibited SMC neointimal accumulation by 37% following angioplasty (Giese et al., 1999). PDGF and its receptors are also increased in the macrophage-rich matrix surrounding polytetrafluoroethylene vascular grafts in baboons (Kraiss et al., 1993) as well as in vein grafts in pigs (Francis et al., 1994). An acute reduction in blood flow and shear stress induces PDGF A chain in the baboon prosthetic grafts (Kraiss et al., 1996), while stenting in the pig arteriovenous bypass graft model was associated with a reduced intimal formation and reduced expression of PDGF (Mehta et al., 1998). Glomerulonephritis As observed in patients with hypercholesterolemia (Billett et al., 1996), PDGF B chain expression is
increased in peripheral blood mononuclear cells in IgA nephropathy and has been shown to be positively correlated with protein secretion (Nakamura et al., 1992). A further analysis of renal biopsy specimens demonstrated that glomerular proliferation as well as clinical measures of disease severity were greater in patients positive for PDGF A and B chain (Taniguchi et al., 1996). Similarly, a marked increase in the expression of the PDGF receptor and a more modest increase in PDGF receptor correlated with the grade of histologic lesion in IgA nephropathy (Gesualdo et al., 1994). Thus, although PDGF is required for glomerular development, its sustained overexpression in human disease and a number of animal models of glomerulonephritis suggests that PDGF may be particularly involved in mesangial cell proliferation and connective tissue deposition (Raines and Ross, 1993; Abboud, 1995; Heldin and Westermark, 1999). The infusion of PDGF-BB, but not PDGF-AA, into normal rats stimulated SMC interstitial proliferation and tubulointerstitial fibrosis (Tang et al., 1996). In the rat Thy-1 model of glomerulonephritis, the infusion of PDGF-BB increased glomerular cell proliferation 32-fold, as well as the glomerular deposition of type IV collagen, laminin, and fibronectin (Floege et al., 1993). Antagonism of PDGF in the same model, with either anti-PDGF antibodies (Johnson et al., 1992) or a PDGF B chain aptamer (Floege et al., 1999), significantly reduced the proliferation of mesangial cells and the glomerular deposition of type IV collagen and fibronectin. Proliferative Retinal Disease Proliferative retinopathy is a common complication of diabetes, a disease in which the increased release of PDGF from platelets has been suggested (Guillausseau et al., 1989). An analysis of the human proliferative retinal membranes of individuals with diabetes demonstrated a significantly increased PDGF A chain level in retinal pigment epithelial cells as well as PDGF B chain level in retinal membranes, while primarily vascular cells were positive for both receptors and, principally, PDGF receptor expressed on retinal pigment epithelial cells (Robbins et al., 1994). A similar distribution was observed in proliferative vitreoretinopathy patients. In a rabbit model of proliferative vitreoretinopathy, the injection of embryo fibroblasts derived from PDGF receptor knockout embryos into the eyes of rabbits that had previously undergone gas vitrectomy failed to induce disease (Andrews et al., 1999). The injection of cells expressing PDGF receptor, but not receptor, replaced the ability to induce proliferative vitreoretinopathy.
PDGF 775 Pulmonary Fibrosis PDGF A and B chain expression is increased in alveolar macrophages of individuals with idiopathic pulmonary fibrosis (Nagaoka et al., 1990) and histiocytosis X (Uebelhoer et al., 1995). The intratracheal injection of PDGF-BB into rats (Yi et al., 1996) and the overexpression of PDGF-BB under the control of the lung-specific surfactant protein C in transgenic mice (Hoyle et al., 1999) stimulate pulmonary mesenchymal and epithelial cell proliferation, collagen deposition and lung fibrosis. Data from the vanadium pentoxide-induced rat injury model demonstrate that expression of the PDGF receptor, but not the receptor, is increased in interstitial SMCs in the lung and precedes the development of the fibroproliferative lung lesion (Bonner et al., 1998). PDGF receptor-inducing activity was present in alveolar macrophages following injury, this inducing activity being blocked by the IL-1 receptor antagonist. Both IL-1 and TNF are increased following lung injury, and mice lacking TNF fail to develop fibroproliferative lesions after asbestos exposure; in addition, their expression of PDGF A chain is reduced (Liu et al., 1998). More specific data supporting a role for PDGF are provided by use of AG1296, the tyrosine kinase inhibitor for the PDGF receptor, in the vanadium pentoxide model of lung injury in which AG1296 reduced lung cell proliferation and was more than 90% effective in preventing the increase in hydroxyproline used as a measure of collagen deposition (Rice et al., 1999). Given the critical role of the PDGF receptor in lung alveogenesis (BostroÈm et al., 1996; Lindahl et al., 1997b) and the induction of the PDGF receptor (Bonner et al., 1998), it would be interesting to test the efficacy of a specific PDGF receptor antagonist in the lung fibrosis. Transplant Rejection PDGF A and B chain levels are increased in human renal rejection (Alpers et al., 1996), as are those of the PDGF and receptors (Fellstrom et al., 1989; Floege et al., 1998). Consistent with the T cell induction of PDGF expression in endothelial cells (Shaddy et al., 1992), PDGF A chain expression is increased in endothelial cells and intimal and medial SMCs in renal vascular rejection, with less prominent PDGF B chain expression in intimal and medial SMCs (Alpers et al., 1996). A strong focal expression of PDGF receptor expression was observed in the intimal SMCs of vessels exhibiting signs of arteriosclerosis in areas adjacent to increased PDGF A chain levels (Floege et al., 1998). Given the prominent expression of the PDGF receptor and PDGF A chain, it would be
interesting to test a PDGF receptor-specific antagonist. Chronic rejection of a rat trachea allograft was significantly inhibited by treatment with a selective PDGF inhibitor that blocks both and receptors (Kallio et al., 1999). An increased expression of PDGF A chain has also been noted in human cardiac allografts in myocytes and vascular structures with a predominance of the long form of the PDGF A chain (Zhao et al., 1995). In a rat model of heterotopic cardiac and aortic allografts, a PDGF receptor tyrosine kinase inhibitor, CGP53716, more selective for the PDGF receptor, reduced the incidence and severity of arteriosclerotic lesions (Sihvola et al., 1999). Other Fibrotic Responses As indicated in Table 2 and previously reviewed (Raines and Ross, 1993), PDGF and its receptors are increased in a number of inflammatory, fibroproliferative disorders, including inflammatory bowel disease, cirrhosis of the liver, myelofibrosis, progressive systemic sclerosis, and rheumatoid arthritis. As is suggested from recent studies of pulmonary fibrosis that implicate IL-1 (Bonner et al., 1998) and TNF in the regulation of PDGF and its receptors, it has recently been demonstrated that the endogenous production of IL-1 regulates PDGF A chain production in fibroblasts from patients with systemic sclerosis (Kawaguchi et al., 1999). PDGF in Tumors and in the Connective Tissue Stromal Response A large number of tumors and transformed cells have been shown to express PDGF and its receptors (see Table 3). Data for a causative role of PDGF and its receptors in tumorigenesis is most convincing in examples of altered expression as a result of the chromosomal rearrangement of either PDGF or its receptor. Deregulation of the PDGF B chain via fusion with the collagen gene COL1A1 has been demonstrated in dermatofibrosarcoma protuberans and giant cell fibroblastoma (Simon et al., 1997). Some of the most malignant tumors of neuroglial origin have been shown to contain amplification of the PDGF receptor (Smits and Funa, 1998). The TEL/PDGF receptor fusion product in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF receptor kinase-dependent signaling pathways (Golub et al., 1994; Carroll et al., 1996). Although arguments have been put forward for an autocrine role of PDGF in the growth of a number of tumor cells (reviewed in Heldin and Westermark,
776 E. W. Raines 1999), it has not been determined whether it plays a critical role in tumor growth and progression. A more convincing argument can, however, be made for a role for PDGF in stimulation of the connective tissue stromal response (Raines and Ross, 1993; Heldin and Westermark, 1999). Stroma formation in nude mice inoculated with non-small cell lung cancer cells expressing elevated levels of PDGF, TGF , and TGF demonstrated prominent fibrous stroma, while those negative for PDGF, TGF , and TGF showed no significant stromal response (Bergh, 1988). Similarly, connective tissue is absent in mice following injection of WM9 melanoma cells devoid of PDGF B chain, while injection of melanoma cells transfected with the B chain cDNA showed abundant connective tissue septa surrounding the tumors (Forsberg et al., 1993).
IN THERAPY
Preclinical ± How does it affect disease models in animals? As detailed above, a number of animal models support a role for PDGF, particularly in connective tissue cell recruitment, in atherosclerosis and restenosis, glomerulonephritis, proliferative retinal disease, transplant rejection, pulmonary fibrosis, and other fibrotic responses, including the stromal response to tumors.
Effects of therapy: Cytokine, antibody to cytokine inhibitors, etc. The infusion of PDGF into animals and the inhibition of PDGF with blocking antibodies to PDGF and its receptors support the concept that PDGF stimulates SMC recruitment, proliferation, and extracellular matrix synthesis in a number of target organs (see the section on Pathophysiological roles).
Pharmacokinetics The intravenous injection of both unlabeled and [I125]PDGF-AB into baboons (Bowen-Pope et al., 1994a) and [I125]PDGF-BB into mice (Cohen et al., 1990) demonstrates rapid clearance with a half-life of less than 2 minutes. This rapid clearance is the result of widespread tissue distribution, metabolism by the liver, and excretion by the kidneys (Cohen et al., 1990). PDGF-AB implanted into subcutaneous wound chambers in rats (Sprugel et al., 1987) and
intraperitoneally, intramuscularly, or subcutaneously in mice (Abdiu et al., 1998) was also cleared rapidly, with a half-life of 12 hours. Maximal detection of PDGF in the blood was observed 2±4 hours after extravascular administration (Abdiu et al., 1998).
Toxicity No toxicity has been observed in clinical trials of PDGF for the treatment of lower extremity ulcers in diabetes (Smiell, 1998).
Clinical results PDGF is currently in use to accelerate the healing of chronic wounds (LeGrand, 1998; Robson et al., 1998; Miller, 1999; Rees et al., 1999). Although PDGF augments granulation tissue formation, fibroblast infiltration, and matrix formation in animal models of defective wound repair (see above), its efficacy in the treatment of human wounds has been limited and may require an approach utilizing a combination of growth factors (Robson et al., 1998).
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LICENSED PRODUCTS PDGF-BB is the active ingredient in REGRANEX (becaplermin) which has been approved in the United States for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply.
