MECHANISMS OF CHONDROCYTE ACTIVATION IN ARTHRITIS

Project: Research project

Project Details

Description

We are working with a synovial factor which induces the synthesis and
secretion of prostaglandin E (PGE) and several neutral proteinases,
including collagenase, by monolayers of cultured articular chondrocytes.
The chondrocyte activating factor (CAF) which does this is closely related
to, if not not identical with, catabolin and interleukin-1 (IL-1). The
mechanism of chondrocyte activation is completely unknown. From what is
known of stimulus-coupled cellular activation in other systems, we may
suspect one of several mechanisms. One such mechanism involves binding of
the agonist to the plasma membrane with subsequent mediation of a second
messenger such as Ca, cyclic AMP or cyclic GMP, producing the activation of
one or more protein kinases. Another involves the acquisition of direct
protein kinase activity by the receptor in the plasma membrane once it
binds the agonist. Certain agents, such as the steroid hormones, penetrate
the cell and travel to the nucleus. Along these lines, we will determine
the type of mechanism through which chondrocytes are activated by our
synovial CAF. Complementary experiments will be conducted with IL-1.

Binding studies will be performed to determine whether activation is
mediated via a cell surface receptor. To determine whether a "classical"
second messenger is involved in signal transduction, we will measure
possible fluxes in the cytosolic concentrations of Ca, cGMP and cAMP during
activation. Possible mediation of these second messengers will also be
examined through the use of specific stimulators and inhibitors of these
putative intermediaries. If these experiments fail to identify a classical
second messenger, the possibility that the receptor gains protein kinase
activity upon binding CAF or IL-1 will be addressed.

This information will help to identify ways of therapeutically preventing
chondrocyte activation.
StatusFinished
Effective start/end date12/1/8611/30/89

ASJC

  • Medicine(all)