Matrix metalloproteinase-13 is required for zebra fish (Danio rerio) development and is a target for glucocorticoids.
Matrix metalloproteinases (MMPs) are endopeptidases that degrade the proteins of the extracellular matrix (ECM). Expression and activity of the MMPs are essential for embryogenesis, where MMPs participate in the normal ECM 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. Zebra fish (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 zebra fish development, with peak expression at 48 h post-fertilization (hpf). Morpholino knockdown studies showed that MMP-13 expression is necessary for normal zebra fish embryogenesis. Acute exposure to dexamethasone and hydrocortisone resulted in abnormal zebra fish 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 zebra fish 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.
Hillegass
Jedd Michael
JM
Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, USA.
Villano
Caren Melissa
CM
Cooper
Keith Raymond
KR
White
Lori Anne
LA
D000595:Amino Acid Sequence; D000818:Animals; D003094:Collagen / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000139:chemically induced / Q000378:metabolism; D003907:Dexamethasone / Q000633:toxicity*; D004487:Edema / Q000139:chemically induced / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects / Q000201:enzymology; D047108:Embryonic Development / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005938:Glucocorticoids / Q000633:toxicity*; D006801:Humans; D006854:Hydrocortisone / Q000633:toxicity*; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D016415:Sequence Alignment; D013997:Time Factors; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D005938:Glucocorticoids; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D003907:Dexamethasone; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D006854:Hydrocortisone