Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade components of the extracellular matrix and play a key role in modulating ocular scarring.
12–14 Expression of MMPs is low in normal cells to allow for healthy connective tissue remodeling, and overexpression of MMPs can lead to fibrosis, cancer,
15 arthritis,
16 and arteriosclerosis.
17 Neutralization of MMP activity also leads to a reduction in cell-mediated collagen contraction
14 and scarring in vivo.
13
Several MMPs, including MMP-2, MMP-9, MMP-13, and MMP-14, are expressed in normal and wounded corneas, and play a critical role in the balance of extracellular matrix turnover during corneal wound healing.
18,19 In cases of corneal vascularization following trauma, Kvanta et al.
20 have shown increased expression of MMP-2 in the limbal region and corneal stroma. Azar et al.
21 have also reported increased MMP-2 and MMP-9 levels during corneal wound healing after LASIK and excimer laser photorefractive keratectomy. In glaucoma, MMPs have been identified in human trabecular meshwork cells, and the balance between MMP and inhibitor activity plays a crucial role in modulating trabecular extracellular matrix and aqueous outflow.
22,23 McCluskey et al.
24 have also reported increased MMP-1, MMP-2, and MMP-3 expression in the bleb capsules surrounding glaucoma implants.
There is now increasing evidence of a link between the MRTF-A/SRF pathway and MMP expression.
25–28 In a recent paper, Esnault et al.
25 have shown that MMP-2, MMP-9, and MMP-14 are all SRF targets in NIH3T3 fibroblasts. Kim et al.
27 and Zhe et al.
28 have also reported that SRF overexpression led to an increase in MMP-2 and MMP-9 levels in hepatocellular cancer and lung fibroblasts respectively. Moreover, Howard et al.
26 have shown that MRTF-A knockdown led to the upregulation of MMP-2 in the presence of transforming growth factor β (TGF-β).
The MRTF-A/SRF transcription pathway is an important upstream regulator of MMP expression in ocular fibrosis (
Fig.). Serum response factor can regulate the gene expression of profibrotic targets, such as MMPs, by both direct and indirect routes. Through the indirect route, SRF can act through the activator protein 1 (AP-1) to modulate the expression of multiple MMP genes.
29,30