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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 Rheum. 2004 Jan; 50(1):247-58.AR

Abstract

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Authors+Show Affiliations

VA Medical Center and University of California, San Diego, CA 92161, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14730623

Citation

Liu, Ru, et al. "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 and Rheumatism, vol. 50, no. 1, 2004, pp. 247-58.
Liu R, Lioté F, Rose DM, et al. 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 Rheum. 2004;50(1):247-58.
Liu, R., Lioté, F., Rose, D. M., Merz, D., & 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 and Rheumatism, 50(1), 247-58.
Liu R, et al. 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 Rheum. 2004;50(1):247-58. PubMed PMID: 14730623.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes. AU - Liu,Ru, AU - Lioté,Frédéric, AU - Rose,David M, AU - Merz,Denise, AU - Terkeltaub,Robert, PY - 2004/1/20/pubmed PY - 2004/2/18/medline PY - 2004/1/20/entrez SP - 247 EP - 58 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 50 IS - 1 N2 - OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/14730623/Proline_rich_tyrosine_kinase_2_and_Src_kinase_signaling_transduce_monosodium_urate_crystal_induced_nitric_oxide_production_and_matrix_metalloproteinase_3_expression_in_chondrocytes_ L2 - https://doi.org/10.1002/art.11486 DB - PRIME DP - Unbound Medicine ER -