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Attenuation of experimental proliferative vitreoretinopathy by inhibiting the platelet-derived growth factor receptor
Y Ikuno1, F L Leong, A Kazlauskas
1The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Purpose:
The work from numerous laboratories has led to the idea that the growth factors such as platelet-derived growth factor (PDGF) contribute to proliferative vitreoretinopathy (PVR) in experimental models of the disease, as well as in humans. In support of this idea, the authors have previously reported that cells unable to respond to PDGF had a greatly reduced PVR potential, compared with PDGF-responsive versions of the same cells. The goal of this study was to test the effect of blocking the output of the PDGF receptor in an experimental model of PVR.
Methods:
Polymerase chain reaction-based site-directed mutagenesis was used to generate point mutations in the human PDGF alpha receptor (alphaPDGFR) cDNA, which resulted in single amino acid substitutions. These changes were based on naturally occurring point mutations in the c-kit receptor tyrosine kinase, which suppresses the function of wild-type c-kit. A truncated alphaPDGFR was also made, in which the receptor ended just after the juxtamembrane domain. As with the point mutants, truncated receptors have been shown to block the action of wild-type receptors. All the alphaPDGFR mutants were introduced into cells that naturally express the wild-type receptor, and the PDGF-dependent output of the resultant cell lines was determined. In addition, the PVR potential of cell lines expressing the mutant receptors was tested in a PVR rabbit model.
Results:
Although the mutants differed in their ability to suppress PDGF-dependent signaling of the wild-type receptor, each mutant effectively blocked cell cycle progression. When expressed in rabbit conjunctival fibroblasts, a cell line that effectively induces PVR, the mutant receptors blocked PVR to various degrees. The most effective receptor was the truncated mutant.
Conclusions:
These data suggest that the alphaPDGFR plays an important role in PVR. In addition, these mutant receptors appear to have therapeutic potential for prevention of this blinding disease.
Insights
Blocking the platelet-derived growth factor (PDGF) receptor with mutant forms effectively reduced proliferative vitreoretinopathy (PVR) in experimental models. These findings highlight the PDGF receptor
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Platelet-derived growth factor (PDGF) is implicated in proliferative vitreoretinopathy (PVR).
- Cells unresponsive to PDGF exhibit reduced PVR potential.
- Previous studies suggest a critical role for PDGF signaling in PVR pathogenesis.
Purpose of the Study:
- To investigate the therapeutic potential of blocking PDGF signaling.
- To evaluate the effect of inhibiting the PDGF alpha receptor (alphaPDGFR) in an experimental PVR model.
Main Methods:
- Site-directed mutagenesis generated alphaPDGFR mutants with suppressed function.
- Truncated alphaPDGFR variants were engineered to block wild-type receptor activity.
- Mutant alphaPDGFRs were introduced into cells, and their effect on PDGF signaling and PVR induction in a rabbit model was assessed.
Main Results:
- Mutant alphaPDGFRs effectively blocked cell cycle progression.
- Expression of mutant receptors in rabbit conjunctival fibroblasts significantly reduced PVR.
- A truncated alphaPDGFR mutant demonstrated the highest efficacy in blocking PVR.
Conclusions:
- The alphaPDGFR is a key mediator in PVR development.
- Engineered alphaPDGFR mutants show therapeutic promise for preventing PVR.
- Targeting the PDGF receptor offers a potential strategy for treating this blinding condition.
