Title

Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease: Implications for the Mucopolysaccharidoses and Other Connective Tissue Diseases

Document Type

Article

Publication Date

1-1-2008

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-kappaB 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.

Publication Title

The American Journal of Pathology

Volume

172

Issue

1

First Page

112

Last Page

122

PubMed ID

18079441

Comments

This article was published in American Journal of Pathology, Volume 172, Issue 1, January 2008, Pages 112–122.

The published version is available at http://dx.doi.org/10.2353/ajpath.2008.070564

Copyright © 2008 American Society for Investigative Pathology

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