Matrix metalloproteinase-13 (MMP-13) is required for zebrafish (Danio rerio) development and is a target for glucocorticoids

Matrix metalloproteinases (MMPs) are endopeptidases that degrade the proteins of the extracellular matrix. Expression and activity of the MMPs are essential for embryogenesis, where MMPs participate in the normal extracellular matrix remodeling that occurs during tissue morphogenesis and development. Studies have demonstrated that MMP gene expression is inhibited by glucocorticoids in mammalian cell culture systems, and that exposure to glucocorticoids causes developmental abnormalities in several species. Therefore, we proposed that glucocorticoids impede normal development through alteration of MMP expression. Zebrafish (Danio rerio) were used as a model to study MMP-13 expression both during normal embryogenesis and following acute exposure to two glucocorticoids, dexamethasone and hydrocortisone. MMP-13 is one of three collagenases identified in vertebrates that catalyzes the degradation of type I collagens at neutral pH. MMP-13 expression varied during zebrafish development, with peak expression at 48 hours post fertilization (hpf). Morpholino knockdown studies showed that MMP-13 expression is necessary for normal zebrafish embryogenesis. Acute exposure to dexamethasone and hydrocortisone resulted in abnormal zebrafish development including craniofacial abnormalities, altered somitogenesis, blood pooling and pericardial and yolk sac edema as well as increased MMP-13 mRNA and activity at 72 hpf. In situ hybridization experiments were used to confirm the increase in MMP-13 expression following glucocorticoid treatment and showed elevated MMP-13 expression in the rostral trunk, brain, eye, heart, and anterior kidney of treated embryos. These data demonstrate that normal zebrafish embryogenesis requires MMP-13 and that dexamethasone and hydrocortisone modulate the expression of this gene, leading to increased activity and potentially contributing to subsequent dysmorphogenesis.