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ToxSci Advance Access published online on August 28, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm192
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

JM Hillegass&, CM Villano&, KR Cooper& and LA White*

& Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901

* To whom all correspondence should be addressed. Department of Biochemistry and Microbiology, 76 Lipman Dr., Rutgers, The State University of NJ, New Brunswick, NJ 08901. phone: 732-932-9763. fax: 732-932-8965. email: lawhite{at}aesop.rutgers.edu

Received October 26, 2006; revision received July 23, 2007; accepted July 23, 2007


  Abstract

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.

Key Words: Matrix metalloproteinases; MMPs; glucocorticoids; zebrafish; development.


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J. M. Hillegass, C. M. Villano, K. R. Cooper, and L. A. White
Glucocorticoids Alter Craniofacial Development and Increase Expression and Activity of Matrix Metalloproteinases in Developing Zebrafish (Danio rerio)
Toxicol. Sci., April 1, 2008; 102(2): 413 - 424.
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