Molecular Pathogenesis of Genetic and Inherited Diseases Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease Implications for the Mucopolysaccharidoses and Other Connective Tissue Diseases

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 factorB 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 2008, 172:112–122; DOI: 10.2353/ajpath.2008.070564) The mucopolysaccharidoses (MPS) are a group of 11 distinct lysosomal storage disorders attributable to defective catabolism of glycosaminoglycans (GAGs), leading to severe joint and bone disease. Our previous studies in MPS animal models showed that inflammation is a critical aspect of these disorders, secondary to GAG accumulation. As part of this inflammatory cascade, tumor necrosis factor (TNF) and other inflammatory cytokines [eg, interleukin (IL-1 )] are released from chondrocytes, resulting in apoptosis. In addition, matrix metalloproteinases (MMPs) are released, contributing to the joint and bone destruction. Lipopolysaccharide (LPS), a molecule that is structurally similar to GAGs, stimulates a signaling pathway that is pivotal to the pathogenesis of many chronic inflammatory diseases, including rheumatoid arthritis (RA). LPS signaling occurs through Toll-like receptor 4 (TLR4) and can result in the release of TNFand other proinflammatory cytokines. Based on these observations, we put forth a hypothesis suggesting that GAG accumulation in MPS connective tissues induces TNFrelease and inflammation through stimulation of the LPS signaling pathway. Notably, although TNFpromotes apoptosis in cartilage, this cytokine has a proliferative effect in synovial cells. This would be consistent with the hyperplasia observed in MPS synovial tissue. Abnormal GAG metabolism has been observed in several common autoimmune diseases, including RA, scleroderma, systemic lupus erythematosus, and others. For example, patients with RA have elevated concentrations of GAGs in blood and synovial fluid, and the destruction of joints in these patients correlates positively with high GAG levels in synovial fluid. Injection of