Mucopolysaccharidosis VII (MPS VII) is due to mutations within the gene encoding the lysosomal
enzyme β-
glucuronidase, and results in the accumulation of
glycosaminoglycans. MPS VII causes aortic dilatation and
elastin fragmentation, which is associated with upregulation of the elastases
cathepsin S (CtsS) and
matrix metalloproteinase 12 (MMP12). To test the role of these
enzymes, MPS VII mice were crossed with mice deficient in CtsS or MMP12, and the effect upon aortic dilatation was determined. CtsS deficiency did not protect against aortic dilatation in MPS VII mice, but also failed to prevent an upregulation of
cathepsin enzyme activity. Further analysis with substrates and inhibitors specific for particular
cathepsins suggests that this
enzyme activity was due to CtsB, which could contribute to
elastin fragmentation. Similarly, MMP12 deficiency and deficiency of both MMP12 and CtsS could not prevent aortic dilatation in MPS VII mice. Microarray and
reverse-transcriptase real-time PCR were performed to look for upregulation of other elastases. This demonstrated that
mRNA for
complement component D was elevated in MPS VII mice, while immunostaining demonstrated high levels of
complement component C3 on surfaces within the aortic media. Finally, we demonstrate that neonatal
intravenous injection of a retroviral vector encoding β-
glucuronidase reduced aortic dilatation. We conclude that neither CtsS nor MMP12 are necessary for
elastin fragmentation in MPS VII mouse aorta, and propose that CtsB and/or
complement component D may be involved.
Complement may be activated by the GAGs that accumulate, and may play a role in signal transduction pathways that upregulate elastases.