title: The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: possible role in osteoarthritic cartilage degradation.
abstract: The degradation of osteoarthritic (OA) cartilage is likely related to the synthesis and the release of catabolic factors by chondrocytes. Nitric oxide (NO) has recently been suggested as playing a role in cartilage degradation. Since NO production is largely dependent on stimulation by IL-1, its effects on factors regulating the IL-1 biological activity, such as IL-1ra, are of the utmost importance. This study examined and compared the level of NO production by normal and OA cartilage and chondrocytes, as well as studied the effect of IL-1-induced NO production on the synthesis and steady-state mRNA of interleukin-1 receptor antagonist (IL-1ra). The NO baseline production by normal cartilage explants was undetectable but inducible by rhIL-1 beta. OA cartilage spontaneously produced NO. About a two-fold increase in NO production was found in OA rhIL-1 beta-stimulated (0.5-100 units/ml) cartilage as compared with the similarly stimulated normal cartilage. on chondrocytes rhIL-1 beta-stimulation (0.5-100 units/ml) produced a dose-dependent enhancement of both NO production and IL-1ra synthesis. Treatment with 200 microM N(g)-monomethyl-L-arginine (L-NMA), a well known NO synthase inhibitor, induced over 70% inhibition of the NO production and a marked increased IL-1ra synthesis (average of 84%) and expression (mRNA level). Inhibition of prostaglandin synthesis by indomethacin had no effect on both the NO production or the IL-1ra level. In the present study, we demonstrated the capacity of OA cartilage to produce a larger amount of NO than the normal controls, both in spontaneous and IL-1-stimulated conditions. These data support the notion that, in vivo, OA chondrocytes are stimulated by factors, possibly IL-1, which in turn may induce the expression of NO synthase, thus the synthesis of NO itself. Importantly, our results showed that the elevation of of NO production may be an important factor in the pathophysiology of OA since it can reduce IL-1ra synthesis by chondrocytes. As such, an increased level of IL-1, associated with a decreased IL-1ra level, may be responsible for the stimulation of OA chondrocytes by this cytokine, leading to an enhancement of cartilage matrix degradation.
authors.affiliation: Louis-Charles Simard Research Center, Notre-Dame Hospital, Department of Medicine, University of Montreal, Quebec, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Pelletier
authors.forename: F
authors.initials: F
authors.lastname: Mineau
authors.forename: P
authors.initials: P
authors.lastname: Ranger
authors.forename: G
authors.initials: G
authors.lastname: Tardif
authors.forename: J
authors.initials: J
authors.lastname: Martel-Pelletier
mesh_terms: D000368:Aged; D001483:Base Sequence; D015152:Blotting, Northern; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003720:Densitometry; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis*; D015345:Oligonucleotide Probes / Q000737:chemistry; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D009569:Nitric Oxide