Interleukin 17 induced nitric oxide suppresses matrix synthesis and protects cartilage from matrix breakdown.
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-alpha, 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-1alpha. 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.


CONCLUSIONS
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-I and IL-17, their downstream signaling pathways are distinct and appear to be affected by extracellular matrix degradation.
Department of Molecular Oncology, Genentech Inc, South San Francisco California 94080-4990, USA.
Liping
L
Cai
Pam
P
Suboc
Deborah A
DA
Hogue
David T W
DT
Fei
Ellen H
EH
Filvaroff
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D011509:Proteoglycans / Q000378:metabolism; D013552:Swine
D017077:Culture Media, Conditioned; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D020381:Interleukin-17; D011509:Proteoglycans; D009569:Nitric Oxide; D003907:Dexamethasone; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3