Possible positive autocrine feedback in the prereplicative phase of human fibroblasts

Paulsson, Ylva; Hammacher, Annet; Heldin, Carl‐Henrik; Westermark, Bengt

doi:10.1038/328715a0

Cited by 216 publications

(94 citation statements)

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“…11C; Kawaguchi et al 1999). This appears to contrast with normal fibroblasts in which transient PDGF-A expression occurs after exposure to mitogens (Paulsson et al 1987). Another feature that distinguishes scleroderma fibroblasts from their normal counterparts is that TGF␤ increases the expression of PDGFR-␣ and enhances the mitogenic effect of PDGF-A in the former (Fig.…”

Section: Dermal Fibrosismentioning

confidence: 63%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

2,048

1,898

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Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-␣ signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-␤ signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial-mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.Platelet-derived growth factor (PDGF) was identified more than three decades ago as a serum growth factor for fibroblasts, smooth muscle cells (SMCs), and glia cells (Kohler and Lipton 1974;Ross et al. 1974;Westermark and Wasteson 1976). Human PDGF was originally identified as a disulfide-linked dimer of two different polypeptide chains, A and B, separable using reversed phase chromatography (Johnsson et al. 1982). The B-chain (PDGF-B) was characterized by amino acid sequencing, revealing a close homology between PDGF-B and the product of the retroviral oncogene v-sis of simian sarcoma virus (SSV) (Doolittle et al. 1983;Waterfield et al. 1983). Subsequent studies confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B and that autocrine PDGF activity was sufficient for SSV transformation in vitro. This was a paradigm-shifting discovery about the relationship between neoplastic cell transformation and normal growth control. For the first time, the importance of autocrine growth stimulation in neoplastic transformation was demonstrated. As discussed below, it is now well established that autocrine PDGF stimulation plays a role also in some human cancers.PDGF-A was characterized by cDNA cloning ). This resolved a paradoxical lack of correlation between secretion of PDGF-like growth factors from tumor cell lines and their expression of c-sis; it turned out that most such cell lines express PDGF-A and secrete PDGF-AA homodimers ). Together with the demonstration that PDGF-BB homodimers are produced by SSV-transformed or PDGF-Bexpressing cells, these results showed that the PDGF...

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Section: Dermal Fibrosismentioning

confidence: 63%

Role of platelet-derived growth factors in physiology and medicine

Andræ¹,

Gallini²,

Betsholtz³

2008

Genes Dev.

2,048

1,898

View full text Add to dashboard Cite

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“…This gene also contains GC sequences within its upstream region. It is induced by serum but is activated later than the immediate-early response genes (49). Although there is no direct indication that Krox-24 or Krox-20 might modulate the expression of any of these genes in vivo, this possibility is worth investigation.…”

mentioning

confidence: 99%

The serum-inducible mouse gene Krox-24 encodes a sequence-specific transcriptional activator.

Lemaire¹,

Vesque²,

Schmitt³

et al. 1990

Mol. Cell. Biol.

239

130

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The mouse gene Krox-24 is transiently activated during cell cycle reentry. It encodes a protein with three zinc fingers similar to those of the transcription factor Sp1. Here we present a biochemical characterization of the gene products. Krox-24 mRNA is translated into two proteins of 82 and 88 kilodaltons, designated p82Krox-24 and p88Krox-24, respectively. p82Krox-24 is initiated at the first AUG codon of the open reading frame, whereas synthesis of p88Krox-24 starts at a non-AUG codon located upstream. Both proteins were synthesized in HeLa cells infected with recombinant vaccinia viruses expressing Krox-24 cDNAs. Under these conditions, they were found phosphorylated on serine residues and glycosylated. The availability of the proteins made possible the determination of the DNA recognition sequence. In vitro, Krox-24 bound specifically to the sequence 5'-GCG(C/G)GGGCG-3'. This sequence is similar but not identical to the Sp1 target sequence. Insertion of an oligomer for the binding site in cis, close to the herpes simplex virus thymidine kinase promoter, rendered this promoter responsive to Krox-24. Krox-24 is therefore a sequence-specific transcriptional activator. Krox-24-binding sites were found upstream of several serum-inducible genes, raising the possibility that Krox-24 is involved in the regulation of these genes.

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“…PDGF is produced by many cells including macrophages 45 and fibroblasts 46 and recruits neutrophils, macrophages, and fibroblasts to the site of injury. 47 IL-1 is secreted by many cells including monocytes and macrophages, promotes cellular aggregation at the inflammatory site, and is involved in wound repair and fibrosis.…”

mentioning

confidence: 99%

Early inflammatory response of knee ligaments to prolotherapy in a rat model

Jensen

Rabago

Best

et al. 2008

Journal Orthopaedic Research

118

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Prolotherapy is an alternative injection-based therapy for chronic musculoskeletal pain. Three different proliferants, D-glucose (dextrose), phenol-glucose-glycerine (P2G), and sodium morrhuate, used in prolotherapy are hypothesized to strengthen and reorganize chronically injured soft tissue and decrease pain through modulation of the inflammatory process. Our hypothesis is that commonly used prolotherapy solutions will induce inflammation (leukocyte and macrophage infiltration) in medial collateral ligaments (MCLs) compared to needlestick, saline injection, and no-injection controls. MCLs of 84 Sprague-Dawley rats were injected one time at both the tibial and femoral insertions. Immunohistochemistry (IHC) was used to determine the inflammatory response at three locations (tibial and femoral insertions and midsubstance) 6, 24, and 72 h after dextrose injection compared to saline-and no-injection controls and collagenase (positive control) (n ¼ 4). qPCR was used to analyze gene expression 24 h postinjection (n ¼ 4). Sodium morrhuate, P2G, and needlestick control were also investigated after 24 h (n ¼ 4). In general, inflammation (CD43þ, ED1þ, and ED2þ cells) increased after prolotherapy injection compared to no-injection control but did not increase consistently compared to saline and needlestick control injections. This response varied by both location and proliferant. Inflammation was observed at 6 and 24 h postinjection but was resolved by 72 h compared to no-injection controls (p < 0.05). CD43þ leukocytes and ED2þ macrophages increased compared to needlestick and saline-injection control, respectively, 24 h postinjection (p < 0.05). Prolotherapy injections created an inflammatory response, but this response was variable and overall, not uniformly different from that caused by saline injections or needlestick procedures. ß

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Possible positive autocrine feedback in the prereplicative phase of human fibroblasts

Cited by 216 publications

References 0 publications

Role of platelet-derived growth factors in physiology and medicine

Role of platelet-derived growth factors in physiology and medicine

The serum-inducible mouse gene Krox-24 encodes a sequence-specific transcriptional activator.

Early inflammatory response of knee ligaments to prolotherapy in a rat model

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