Studies on cartilage and bone disease in Mucopolysaccharidoses and Mucolipidoses

Abstract

Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystem involvement. In MPS, deficiencies of glycosaminoglycans (GAGs) degrading enzymes lead to intralysosomal GAG storage. In the MLs, defective trafficking of lysosomal enzymes to the lysosome, leads to accumulation of a combination of GAGs and several other complex molecules. GAGs are degraded by enzymes, in part extracellularly and in part intracellularly in the lysosomes after uptake through endocytosis. Intralysosomal storage in MPS and ML patients gives rise to loss of cellular function by disturbed autophagy, polyubiquitination, mitochondrial dysfunction, inflammation, apoptosis, and loss of lysosomal membrane integrity, followed by tissue damage and organ dysfunction. These events eventually determine the clinical symptoms observed in the patients. Skeletal abnormalities are common in MPS and ML patients and originate from intralysosomal storage in cells of the cartilage, bones and ligaments. A major problem of these tissues is that they are difficult to treat as vascularization is poor and cell renewal (division) is slow. The existing therapies for these diseases are unable to fully correct or prevent the abnormalities occurring in bones and cartilage. To enable development of new therapies it is crucial to understand the processes involved in abnormal cartilage and bone development as observed in MPS and ML and relate them to normal skeletal development. The aim of this thesis is to create a better understanding of the etiology and pathophysiology of cartilage and bone development in patients with mucopolysaccharidosis and mucolipidosis, the clinical course and therapeutic challenges of skeletal disease in these disorders