Mechanism of glycosaminoglycan-mediated bone and joint disease: Implications for the mucopolysaccharidoses and other connective tissue diseases

Calogera M. Simonaro, Marina D'Angelo, Xingxuan He, Efrat Eliyahu, Nataly Shtraizent, Mark E. Haskins, Edward H. Schuchman

Research output: Contribution to journalArticlepeer-review

186 Scopus citations

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-κB 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.

Original languageEnglish
Pages (from-to)112-122
Number of pages11
JournalAmerican Journal of Pathology
Volume172
Issue number1
DOIs
StatePublished - Jan 2008

Fingerprint

Dive into the research topics of 'Mechanism of glycosaminoglycan-mediated bone and joint disease: Implications for the mucopolysaccharidoses and other connective tissue diseases'. Together they form a unique fingerprint.

Cite this