PUBLICATION
Excessive activity of cathepsin K is associated with the cartilage defects in a zebrafish model for mucolipidosis II
- Authors
- Petrey, A.C., Flanagan-Steet, H., Johnson, S., Fan, X., De la Rosa, M., Haskins, M.E., Nairn, A.V., Moremen, K.W., and Steet, R.
- ID
- ZDB-PUB-111117-4
- Date
- 2012
- Source
- Disease models & mechanisms 5(2): 177-190 (Journal)
- Registered Authors
- Fan, Xiang, Flanagan-Steet, Heather, Johnson, Stephen L., Steet, Richard
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Base Sequence
- Cartilage/abnormalities
- Cartilage/embryology
- Cartilage/metabolism*
- Cathepsin K/antagonists & inhibitors
- Cathepsin K/genetics
- Cathepsin K/metabolism*
- Collagen Type II/genetics
- Collagen Type II/metabolism
- Craniofacial Abnormalities/embryology
- Craniofacial Abnormalities/genetics
- Craniofacial Abnormalities/metabolism
- Disease Models, Animal
- Extracellular Matrix Proteins/genetics
- Extracellular Matrix Proteins/metabolism
- Humans
- Mannosephosphates/biosynthesis
- Mucolipidoses/genetics
- Mucolipidoses/metabolism*
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 22046029 Full text @ Dis. Model. Mech.
Citation
Petrey, A.C., Flanagan-Steet, H., Johnson, S., Fan, X., De la Rosa, M., Haskins, M.E., Nairn, A.V., Moremen, K.W., and Steet, R. (2012) Excessive activity of cathepsin K is associated with the cartilage defects in a zebrafish model for mucolipidosis II. Disease models & mechanisms. 5(2):177-190.
Abstract
The severe pediatric disorder, mucolipidosis II (ML-II; I-cell disease), is caused by defects in mannose 6-phosphate (Man-6-P) biosynthesis. Patients with ML-II exhibit multiple developmental defects including skeletal, craniofacial and joint abnormalities. To date, the molecular mechanisms that underlie these clinical manifestations are poorly understood. Taking advantage of a zebrafish model for ML-II, we previously showed that the cartilage morphogenesis defects in this model are associated with altered chondrocyte differentiation and excessive deposition of type II collagen, indicating that aspects of development that rely on proper extracellular matrix homeostasis are sensitive to decreases in Man-6-P biosynthesis. To further investigate the molecular bases for the cartilage phenotypes, we analyzed the transcript abundance of several genes in chondrocyte-enriched cell populations isolated from wild-type WT and ML-II zebrafish embryos. Increased levels of cathepsin and matrix metalloproteinase (MMP) transcripts were noted in ML-II cell populations. This increase in transcript abundance corresponded with elevated and sustained activity of several cathepsins (K, L and S) and MMP-13 during early development. Unlike MMP-13, in which higher levels of enzyme was also detected, sustained activity of cathepsin K appeared to result from abnormal processing and activation of this enzyme at later stages. Inhibition of cathepsin K activity by pharmacological or genetic means not only reduced the activity of this enzyme but led to a broad reduction in additional protease activity, significant correction of the cartilage morphogenesis phenotype and reduced type II collagen staining in ML-II embryos. Our findings suggest a central role for excessive cathepsin K activity in the developmental aspects of ML-II cartilage pathogenesis and highlight the utility of the zebrafish system to address the biochemical underpinnings of metabolic disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping