Drs. Liu and Lioté contributed equally to this work.
Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal–induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes
Article first published online: 9 JAN 2004
Copyright © 2004 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 50, Issue 1, pages 247–258, January 2004
How to Cite
Liu, R., Lioté, F., Rose, D. M., Merz, D. and Terkeltaub, R. (2004), Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal–induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes. Arthritis & Rheumatism, 50: 247–258. doi: 10.1002/art.11486
- Issue published online: 9 JAN 2004
- Article first published online: 9 JAN 2004
- Manuscript Accepted: 13 OCT 2003
- Manuscript Received: 18 MAR 2003
- Department of Veterans Affairs
- NIH. Grant Numbers: HL-61731, R03-AR-49416-10, P01-AG-07996
- Arthritis Foundation
- University of California, San Diego
- Medicine Education Research Foundation
- Stein Institute for Research on Aging, Assistance Publique Hôpitaux de Paris, Paris 7 University
- Philippe Foundation
Articular deposition of monosodium urate monohydrate (MSU) crystals may promote cartilage and bone erosion. Therefore, the aim of this study was to determine how MSU crystals stimulate chondrocytes.
Nitric oxide (NO) release, and expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase 3 (MMP-3) were assessed in cultured chondrocytes treated with MSU. MSU-induced functional signaling by specific protein kinases (p38, Src, and the focal adhesion kinase [FAK] family members proline-rich tyrosine kinase 2 [Pyk-2] and FAK) was also examined using selective pharmacologic inhibitors and transfection of kinase mutants.
MSU induced MMP-3 and iNOS expression and NO release in chondrocytes in a p38-dependent manner that did not require interleukin-1 (IL-1), as demonstrated by using IL-1 receptor antagonist. MSU induced rapid tyrosine phosphorylation of Pyk-2 and FAK, their adaptor protein paxillin, and interacting kinase c-Src. Pyk-2 and c-Src signaling both mediated p38 MAPK activation in response to MSU. Pyk-2 and c-Src signaling played a major role in transducing MSU-induced NO production and MMP-3 expression. But, despite the observed FAK phosphorylation, a selective pharmacologic FAK inhibitor and a FAK dominant-negative mutant both failed to block MSU-induced NO release or MMP-3 expression in parallel experiments.
In chondrocytes, MSU crystals activate a signaling kinase cascade typically employed by adhesion receptors that involves upstream Src and FAK family activation and downstream p38 activation. In this cascade, Pyk-2, Src, and p38 kinases transduce MSU-induced NO production and MMP-3 expression. Our results identify Pyk-2 and c-Src as novel sites for potential therapeutic intervention in cartilage degradation in chronic gout.