Heparan sulfate in Degenerating Joint Diseases

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In this project we aim to investigate the role of heparan sulfate (HS) in degenerating joint diseases. Besides their structural function, HS of the extracellular proteoglycan network regulate growth factor signaling and bind to many extracellular proteins. Investigating a mouse line, in which the HS synthesizing enzyme Ext1 can be clonally deleted in chondrocytes, we found clones of hypertrophic cells in the articular surface, indicating a function HS in maintaining the joint surface. Here we plan to introduce cartilage degenerating diseases in Ext1 deficient mice. A hypomorpic allele of Ext1 will be used to generally decrease HS levels across the articular surface. In parralel clonal deletion of Ext1 will produce cells lacking HS. We will induce osteoarthritis (OA), rheumathoid arthritis (RA) and psoriasis arthritis (PsA) using crucial ligament dissections (OA) and the transgenic mouse lines hTNFtg and TTP-/- for RA and PsA, respectively. The progression of the disease will be followed using histological and molecular methods. Care will be taken to identify alterations in inflammation, protease levels and signaling factors implicated in joint diseases. The interaction of identified proteins with HS will be analyzed biochemically. As loss Syndecan-4, a carrier of HS in chondrocytes, has been shown to protect against OA, we will investigate OA progression in Ext1;Syndecan-4 mutants and in mutants with altered patterns of sulfation.