Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II
Open Access
- 1 March 2012
- journal article
- Published by The Company of Biologists in Disease Models & Mechanisms
- Vol. 5 (2), 177-190
- https://doi.org/10.1242/dmm.008219
Abstract
SUMMARY The severe pediatric disorder mucolipidosis II (ML-II; also known as 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 of 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 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, for which higher levels of protein were detected, the sustained activity of cathepsin K at later stages seemed to result from its abnormal processing and activation. 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.Keywords
This publication has 47 references indexed in Scilit:
- Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomesMolecular Biology of the Cell, 2011
- Disruption of the Man‐6‐P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome BiogenesisTraffic, 2011
- Transcript Analysis of Stem CellsMethods in Enzymology, 2010
- Upregulation of elastase activity in aorta in mucopolysaccharidosis I and VII dogs may be due to increased cytokine expressionMolecular Genetics and Metabolism, 2010
- Neuronal loss and brain atrophy in mice lacking cathepsins B and LProceedings of the National Academy of Sciences of the United States of America, 2002
- Features of mono‐ and multinucleated bone resorbing cells of the zebrafish Danio rerio and their contribution to skeletal development, remodeling, and growthJournal of Morphology, 2001
- Cartilage proteoglycansSeminars in Cell & Developmental Biology, 2001
- Biosynthesis and processing of cathepsin K in cultured human osteoclastsBone, 2001
- Human Osteoclast Cathepsin K Is Processed Intracellularly Prior to Attachment and Bone ResorptionJournal of Bone and Mineral Research, 2001
- Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)JCI Insight, 2000