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Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII

Lachlan J Smith1, Guilherme Baldo, Susan Wu

  • 1Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. lachlans@mail.med.upenn.edu

Molecular Genetics and Metabolism
|April 20, 2012
PubMed

Insights

Mucopolysaccharidosis type VII (MPS VII) involves GAG accumulation and spine issues. Upregulated cathepsins and altered collagen II in MPS VII dogs suggest protease inhibition may treat spine disease.

Area of Science:

  • Biochemistry
  • Genetics
  • Orthopedics

Background:

  • Mucopolysaccharidosis type VII (MPS VII) results from beta-glucuronidase deficiency, causing glycosaminoglycan (GAG) buildup and multisystemic disease.
  • Spinal complications in MPS VII include kyphoscoliosis and cord compression due to intervertebral disk and vertebral body abnormalities.
  • Pathophysiological mechanisms for spinal changes in MPS VII remain unclear, though GAG binding to Toll-like receptor 4 (TLR4) is a potential factor.

Purpose of the Study:

  • Investigate the role of destructive proteases, specifically cathepsins, in spinal pathogenesis of MPS VII.
  • Examine the expression of cathepsins, TLR4, and collagen II in MPS VII canine spines.
  • Correlate findings in MPS VII dogs with human MPS VII spinal pathology.

Main Methods:

  • Assessed cathepsin B and K activity in the annulus fibrosus of MPS VII dog intervertebral disks.
  • Quantified mRNA levels for cathepsins, TLR4, and collagen II in MPS VII dog spinal tissues.
  • Examined spinal autopsy tissue from a human MPS VII patient for comparative analysis.

Main Results:

  • MPS VII dog intervertebral disks showed significantly elevated cathepsin B (117-fold) and cathepsin K (2-fold) activities.
  • Elevated mRNA levels for cathepsins and TLR4 were observed in the annulus fibrosus of MPS VII dogs.
  • MPS VII dogs exhibited increased collagen II mRNA in epiphyses, indicating delayed cartilage-to-bone conversion.
  • Human MPS VII spine showed similar cartilage accumulation and vertebral abnormalities.

Conclusions:

  • Spine disease in MPS VII may involve the upregulation of destructive proteases like cathepsins.
  • The findings suggest a potential role for GAG accumulation and TLR4 in MPS VII spinal pathology.
  • Inhibiting cathepsins could be a therapeutic strategy for reducing spinal disease in MPS VII patients.

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