CHONDROCYTES, NITRIC OXIDE, IL-1 &HYALURONAN BREAKDOWN

Project: Research project

Project Details

Description

Articular chondrocytes mount a pleiotropic response to interleukin-1 (IL-
1), which includes the increased synthesis of prostaglandins and matrix
metalloproteinases, but a decreased synthesis of matrix macromolecules.
Fragments of articular cartilage undergo an autolytic response to IL-1, in
which proteoglycans are released from the matrix; the precise mechanisms
of matrix breakdown remain unclear. The depolymerization of hyaluronan is
particularly mysterious, as no extracellular, neutral hyaluronidase is
found in the joint.

We have recently made the novel observation that articular chondrocytes
synthesize very large quantities of the free radical nitric oxide (.NO)
following treatment with IL-1. In attempting to identify a role for . NO
in cartilage metabolism, we have noted that .NO degrades hyaluronan in
vitro. This invites the hypothesis that the breakdown of hyaluronan by
chondrocyte-derived .NO accounts for at least some of the loss of
proteoglycans from IL-1 treated cartilage. The present application
addresses this hypothesis; we propose to do so at three levels.

First, the chemical breakdown of hyaluronan by .NO will be investigated by
viscometry and size-exclusion chromatography. Second, the ability of cell
cultures of articular chondrocytes to degrade hyaluronan in an .NO-
dependent manner will be studied. Third, the ability of organ cultures of
articular cartilage to degrade their own endogenous hyaluronan, and to
release proteoglycans from their matrix, in .NO-dependent manner will be
studied.

Should the results of these investigations support a role for .NO in
cartilage catabolism, they will identify a novel target for therapeutic
intervention in the arthritic joint.
StatusFinished
Effective start/end date4/1/943/31/97

ASJC

  • Medicine(all)