Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

Abstract

Pterygia are inflammatory, invasive, and proliferative lesions of the human ocular surface in which the matrix metalloproteinase (MMP) collagenase-1 (MMP-1) is highly expressed. Pterygia development may involve MMP-1 activity against interstitial fibrillar collagen, an abundant extracellular matrix component of the cornea, and its induction by ultraviolet light (UVB). We examined the pathways responsible for enhanced expression of MMP-1 in pterygium epithelial cells after UVB exposure and/or treatment with chemical inhibitors of mitogen-activated protein kinases or epidermal growth factor receptor. The induction of MMP-1 by UVB was comparable to that mediated by heparin-binding epidermal growth factor-like growth factor and epidermal growth factor. The epidermal growth factor receptor inhibitor PD153035 partially blocked the UVB-mediated induction of MMP-1 and totally abrogated its production after stimulation with either heparin-binding epidermal growth factor-like growth factor or epidermal growth factor. UVB exposure enhanced the phosphorylated form of ERK1/2 in a time-dependent manner whereas the ERK1/2 inhibitor PD98059 decreased this induction by at least fivefold. Transcripts for c-jun and c-fos were detected as early as 2 hours after UVB exposure and were suppressed by PD98059. The identification of a specific intracellular signaling pathway responsible for the enhanced production of a key enzyme that denatures intact fibrillar collagen has important implications for understanding the pathophysiology and future therapy for pterygia. Pterygium is a condition of the ocular surface characterized by squamous cell metaplasia and goblet cell hyperplasia. The lesion consists of a wing-shaped mass of fibrovascular conjunctival tissue that invades the normal cornea. Other obvious pathological changes include activation of stromal fibroblasts, a persistent inflammatory component, elastotic degeneration, and destruction of collagenous barriers such as Bowman's layer. Pterygia are particularly prevalent in heavily sun-exposed individuals in whom extensive epidemiological studies link this disease to excessive ultraviolet (UV) radiation. 1-5 Despite this evidence, there is still controversy regarding the actual trigger for the development of pterygia and whether or not there is a genetic predisposition to this disease. 6 Recently, we have identified UVB as an environmental agent likely to be responsible for initiating molecular events that lead to the formation of pterygia. 7,8 From our hypothesis, 9 we postulate that UVB radiation activates cells at or near the limbus. This activation may cause 1) phenotypic alterations in a distinct population of epithelial cells, 2) production of proinflammatory and angiogenic cytokines 7 and growth factors, 8 and 3) increased invasiveness due to enhanced production of matrix metalloproteinases (MMPs) over and above their natural tissue inhibitors (TIMPs). 6,9 -12 To date, we 6,9 -12 and others [13][14][15][16][17] have accumulated data from in vitro culture and in vivo tissue-b...

Ultraviolet Radiation and the Anterior Eye

“…In attempting to elucidate how these processes occur, we began by investigating the role of matrix metalloproteinses (MMPs) in pterygium pathogenesis. [69][70][71][72][73] Matrix metalloproteinses are a family of zinc-dependent endopeptidases that are involved in remodeling of the extracellular matrix and altering cell surface molecules. The actions of MMPs are counterbalanced by tissue inhibitors of metalloproteinases (TIMPs), and MMPs are key mediators of photoaging where they regulate proliferation, cell migration, inflammation, and angiogenesis (see Chui and Coroneo 65 ).…”

“…66 This response is common to the ocular surface (pterygium) and the skin, where UV induces phosphorylation and internalization of the EGFR within minutes of exposure, followed by activation of three mitogen-activated protein kinase (MAPK) pathways: extracellular signal-regulated kinase (ERK), c-jun amino-terminal kinase (JNK), and p38. In pterygium, UV activation of the ERK pathway is shown to induce production of MMP-1, 73,75 whereas activation of the stress-related JNK and p38 pathways contributes to IL-6 and IL-8 induction 72 with overexpression of EGFR 82 contributing to amplification of these signaling pathways. Transcription factors are induced downstream of EGFR and MAPK activation, including activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), which mediate some cellular responses to UV damage (see 66 ).…”

“…The UVB activation of the JNK pathway induces production of c-Jun and combined with c-Fos forms the AP-1 complex responsible for induction of MMP-1. 73 The EGFRinduces NF-kB activation; however, this is believed to occur through signaling pathways involving tumor necrosis factor receptor-interacting protein and NF-kB-inducing kinase. NF-kB mediates UV-induced release of IL-1, IL-6, and TNF-a from cultured human corneal epithelial cells.…”

Short-Term Ultraviolet A Irradiation Leads to Dysfunction of the Limbal Niche Cells and an Antilymphangiogenic and Anti-inflammatory Micromilieu

“…What currently is known about UVA radiation, however, is that it, next to inducing inflammation, is associated furthermore with the oxidative stress in cells, gene mutations, and extracellular matrix remodeling that contribute to the development of skin tumors and pterygium. [24][25][26] Growth factors that have been observed to increase in pterygium specimens include VEGF-A, 27,28 VEGF-C, the master regulator of lymphangiogenesis, 29 and its receptor VEGF-R3. 27 This increase correlates with the higher density of the lymphatic network associated with pterygium recurrence and staging, and is considered a long-term effect of UV irradiation.…”

Occupational skin diseases and prevention among sanitation workers in China

“…Both UVA and UVB destroy vitamin A in skin, which may cause further damage 16 . The eye is most sensitive to UV, exposure of the eye to UV may cause welder's flash or arc eye (photokeratitis) and can lead to cataracts, pterygium and pinguecula formation 17,18 . To a lesser extent, UVB in sunlight also causes photokeratitis ("snow blindness"), and the cornea, the lens and the retina can be damaged.…”