Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease

Abstract

We have previously shown that glycosaminoglycan (GAG) storage in animal models of the mucopolysaccharidoses (MPS) leads to inflammation and apoptosis within cartilage. We have now extended these findings to synovial tissue and further explored the mechanism underlying GAG-mediated disease. Analysis of MPS rats, cats, and/or dogs revealed that MPS synovial fibroblasts and fluid displayed elevated expression of numerous inflammatory molecules, including several proteins important for lipopolysaccharide signaling (eg, Toll-like receptor 4 and lipoprotein-binding protein). The expression of tumor necrosis factor, in particular, was elevated up to 50-fold, leading to up-regulation of the osteoclast survival factor, receptor activator of nuclear factor-B ligand, and the appearance of multinucleated osteoclast-like cells in the MPS bone marrow. Treatment of normal synovial fibroblasts with GAGs also led to production of the prosurvival lipid sphingosine-1-phosphate, resulting in enhanced cell proliferation, consistent with the hyperplastic synovial tissue observed in MPS patients. In contrast, GAG treatment of normal chondrocytes led to production of the proapoptotic lipid ceramide, confirming the enhanced cell death we had previously observed in MPS cartilage. These findings have important implications for the pathogenesis and treatment of MPS and have further defined the mechanism of GAG-stimulated disease. (Am J Pathol

Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network

“…Alterations of several secondary cellular processes have been described as a consequence of the lysosomal accumulation of partially degraded substrates, which trigger different pathologic cascades [54,55].…”

Current and emerging treatments and surgical interventions for Morquio A syndrome: a review

“…There may be a clinical effect of ERT by reducing the proinfammatory factors that are induced when excessive KS results in an abnormal structure of extracellular matrix, relieving arthritis and pain in joints, enabling an increase in physical activity, as described in other types of MPS. 62 ERT with native enzyme could also improve hearing, reduce recurrent infection, and reduce airway narrowing (if the storage materials are released from the cartilage of the airway). While ERT with native enzyme may benefit some MPS IVA patients by arresting some aspects of disease progression, the fundamental problems associated with advanced skeletal deformity and laxity of joints are unlikely to be solved by current ERT with native enzyme.…”

Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands

“…44 Studies of animal models of mucopolysaccharidosis VI suggest that proinflammatory cytokines alter expression of several matrix metalloproteinases, enzymes involved in ECM degradation. 45 In ML III, a variable fraction of lysosomal glycoproteins still acquires the M6P recognition marker and is correctly routed to, and functional within, lysosomes. It is apparently sufficient to maintain some statural growth and to postpone clinical expression of the abnormal ECM signalling.…”