Interleukin 17 Induced Nitric Oxide Suppresses Matrix Synthesis and Protects Cartilage from Matrix Breakdown

LIPING CAI, PAM SUBOC, DEBORAH A. HOGUE, DAVID T.W. FEI, and ELLEN H. FILVAROFF

ABSTRACT.

Objective. To investigate the role of nitric oxide (NO) in basal and cytokine induced cartilage matrix breakdown and synthesis across different species and in chondrocytes cultured as isolated cells or as tissue explants.

Methods. Articular cartilage from bovine, porcine, or human joints was cultured as explants in serum-free media. Explants or monolayer cultures of primary chondrocytes were treated with cytokines in the absence or presence of inhibitors [antibodies to leukemia inhibitory factor (anti-LIF) or tumor necrosis factor-a, dexamethasone, or inhibitors of aggrecanase or NO synthase]. NO production and matrix breakdown and synthesis were measured.

Results. At low concentrations, a novel interleukin 17 (IL-17) family member induced matrix breakdown without altering NO production. Treatment of articular cartilage explants with dexamethasone or anti-LIF blocked NO production by IL-17, but not by IL-1a. Inhibition of NO production in cytokine treated cartilage explants enhanced matrix breakdown and partially overcame suppression of matrix synthesis. In isolated chondrocytes, inhibition of NO production decreased expression of gelatinase and increased expression of stromelysin.

Conclusion. Endogenous NO serves a dual function in cartilage: to protect the tissue from matrix breakdown and to mediate suppression of proteoglycan synthesis by cytokines. Despite the similarities in biological function between IL-1 and IL-17, their downstream signaling pathways are distinct and appear to be affected by extracellular matrix degradation. (J Rheumatol 2002;29:1725-36)

Key Indexing Terms:

NITRIC OXIDE
PROTEOGLYCANS
CYTOKINES
RHEUMATOID ARTHRITIS
CHONDROCYTES
INTERLEUKINS

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From the Departments of Molecular Oncology and Bioanalytical Research and Development, Genentech Inc., South San Francisco, California, USA.

L. Cai, MS, Department of Molecular Oncology; P. Suboc, BA, Department of Bioanalytical Research and Development; D.A. Hogue, MS, Department of Molecular Oncology; D.T.W. Fei, PhD, Department of Bioanalytical Research and Development; E.H. Filvaroff, PhD, Department of Molecular Oncology.

Address reprint requests to Dr. E.H. Filvaroff, Department of Molecular Oncology, MS 72B, 1 DNA Way, South San Francisco, CA 94080-4990. E-mail: filvarof@gene.com

Submitted August 10, 2001; revision accepted January 17, 2002.

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