PATHOGENESIS OF DISEASE IN MUCOPOLYSACCHARIDOSIS I AND VII

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Mucopolysaccharidosis I (MPS I) and MPS VII are lysosomal storage diseases in which glycosaminoglycans (GAG) accumulate due to deficient activity in -Liduronidase and -glucuronidase, respectively. This results in multisystemic disease involving aorta and heart, bone and joints, brain, lung, and numerous other sites. Although existing therapies have reduced many aspects of disease, aorta and the cervical spine have been difficult to treat. Both aorta and spine contain elastin and collagen, which are very important for their structural integrity. We hypothesize that upregulation of proteases that degrade these proteins is a common pathophysiological pathway to disease in aorta and spine. Aortas undergo elastin fragmentation and progressive dilatation, which can result in cardiovascular insufficiency and require surgery. We have previously shown that aortic disease is associated with upregulation of elastases of the cathepsin and matrix metalloproteinase (MMP) families in mouse models of MPS I and MPS VII. A second site that is difficult to treat in MPS is the cervical spine, which can require surgery for stabilization. Radiographs demonstrate that vertebrae have destructive changes, and our preliminary data demonstrates that cathepsins are upregulated in the annulus fibrosus of the intervertebral disc and in articular cartilage. Aim I of this project will further evaluate the pathogenesis of disease in the cervical spine of MPS VII dogs, which will involve structural studies and histopathology of the spine. In addition, the expression of genes involved in synthesis, assembly, or destruction of collagen and elastin will be evaluated in the intervertebral disc and the endplate cartilage of the vertebrae in MPS VII dogs. The second aim of this project will attempt to determine the role of specific proteases in aorta in mice. Both cathepsin S and MMP-12 were markedly upregulated in the aorta of MPS I and MPS VII mice and dogs. MPS VII mice will be crossed with cathepsin S-deficient or MMP-12-deficient mice, and the effect upon aortic dilatation and elastin fragmentation will be evaluated. If a specific gene appears to play a major role in elastin fragmentation, subsequent studies in the future would test the effect of drugs that can inhibit these proteases. These studies may demonstrate that the development of disease in the aorta and the cervical spine in MPS is due to a common mechanism, and may identify a therapy for these difficult-to-treat sites.