Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2020)
Progressive skeletal and connective tissue disease is a major clinical burden in Mucopolysaccharidosis type I (MPS I). Although enzyme replacement therapies are available and improve some aspects of the disease, bone and joint disease is recalcitrant. The underlying pathogenic mechanisms of MPS I skeletal and connective tissue disease, and the basis of the recalcitrance to therapy, remain unknown. The classical view of MPS I describes somatic disease as the direct result of glycosaminoglycan (GAG) accumulation; however, it is now clear that many lysosomal storage disorders involve more complex pathogenic mechanisms than simple GAG storage. In order to understand the pathogenic mechanisms underlying skeletal and connective tissue disease in MPS I, I have used proteomic and genome wide expression studies of the femoral head growth plate cartilage, and functional studies of the murine MPS I model knee joint to identify early pathogenic events. Three and five-week-old mice were used; thus these studies represent a previously-unexamined time point at which underlying pathogenic mechanisms may be discovered. Unbiased iTRAQ differential proteomic and multiple reaction monitoring mass spectrometry approaches identified significant decreases in six key structural and signalling extracellular matrix proteins (biglycan, type I collagen, fibromodulin, lactotransferrin, proline/arginine-rich end leucine-rich repeat protein, and SERPINF1). Genome-wide expression studies in five-week growth plate cartilage revealed fourteen significantly deregulated mRNAs (Adamts4, asporin, chondroadherin, type II collagen, type IX collagen, hyaluronan and proteoglycan link protein, lumican, matrillin 1, matrix metalloproteinase 3, osteoglycin, osteomodulin, prolyl 4-hydroxylase, alpha polypeptide II, proline/arginine-rich end leucine-rich repeat protein, and member RAS oncogene family 32). The involvement of members of the small leucine repeat proteoglycan family (asporin, chondroadherin, osteoglycin, osteomodulin, and proline/arginine-rich end leucine-rich repeat protein) in MPS I disease pathogenesis is novel and intriguing, as these proteins are associated with the pathogenesis of osteoarthritis. Functional studies of the MPS I mouse knee joint suggested that early disruption of the extracellular matrix may predispose skeletal and connective tissues to late-stage degeneration. These results imply that biomechanical failure of chondro-osseous tissue may underlie skeletal and joint disease in MPS I. This represents a novel finding which has clear therapeutic implications.