In vitro and in vivo studies have shown that IL-1 and TNF-a are the predominant catabolic cytokines involved in the destruction of the articular cartilage in OA. The first recognition of IL-1 as a regulator of chondrocyte function stems largely from the early work of Fell and Jubb , who identified a soluble factor, termed "catabolin," in supernatants of normal, noninflamed porcine synovial fragment cultures that stimulated chondrocytes to break down the surrounding cartilage matrix. Similar activities were found in culture supernatants from mononuclear cells and synovium [43,142] and later attributed to IL-1 [140,190]. Subsequent studies in vitro and in vivo have established that IL-1 can stimulate the synthesis of most, if not all, proteinases that destroy cartilage.
The major events in OA pathogenesis are localized within the cartilage itself, and chon-drocytes participate in this destructive process not only by responding to the cytokines released from other joint tissues, but also by synthesizing them [70,74]. Chondrocytes are therefore continuously exposed to the autocrine and paracrine effects of high local concentrations of IL-1 and other inflammatory mediators. Our understanding of basic cellular mechanisms regulating chondrocyte responses to cytokine mediators has come from numerous studies of cartilage fragment or isolated chon-drocyte cultures and from studies with animal models. Chondrocytes in OA cartilage, especially those in clonal clusters, are positive for IL-1 immunostaining [149,220]. Chondrocytes synthesize IL-1 at concentrations that induce the expression of MMPs, aggrecanases, and other catabolic genes, and express IL-1P converting enzyme (caspase-1) and type 1 IL-1 receptor (IL-1RI) . IL-1 colocalizes with TNF-a, MMP-1, -3, -8, and -13, and type II collagen cleavage epitopes in regions of matrix depletion found in OA cartilage [220,236]. The increased sensitivity of OA chondrocytes to IL-1 and TNF-a may be associated with increased levels of IL-1R1 and p55 TNF-R at localized sites [14,233].
Originally known as cachectin, TNF-a, similar to IL-1, acts on chondrocytes in vitro to stimulate the production of matrix-degrading proteinases. On a molar basis, IL-1 is 100- to 1000-fold more potent than TNF-a; however, the two cytokines have strong synergism . For example, intraarticular injection of recombinant IL-1 alone into the joints of rats, mice, or rabbits is sufficient to stimulate the destruction of the articular cartilage. When TNF-a and IL-1 are injected together, cartilage damage far exceeds the extent of damage observed with injection of either cytokine alone (see, for review, ). Work with collagen-induced rheumatoid arthritis (CIA)  has led to the concept that TNF-a drives acute inflammation, while IL-1 has a pivotal role in sustaining inflammation and cartilage erosion. Further work is needed to determine whether cytokine synergism also extends to osteoarthritis .
In addition to inducing the synthesis of MMPs and other proteinases by chondrocytes, IL-1 and TNF-a increase the synthesis of other proinflammatory cytokines such as IL-6, leukemia inhibitory factor (LIF), IL-17, and IL-18, and chemokines, including IL-8 (see, for review, [70,74]). They also upreg-ulate the production of nitric oxide (NO) via inducible nitric oxide synthetase (iNOS, or NOS2) and prostaglandin E2 (PGE2) by stimulating the expression or activities of cyclooxygenase (cOx)-2, microsomal PGE synthase-1 (mPGES-1), and soluble phospho-lipase A2 (sPLA2). Although PGE2 and NO have been well characterized as proinflamma-tory mediators, they may also act protectively in chondrocyte survival and in responses to mechanical stress [57,110]. The mechanisms of crosstalk between prostaglandins and NO that regulate chondrocyte function have been reviewed recently . In the production of prostaglandins, mPGES-1, which is increased in OA cartilage, is a major player [108,118, 136]. In addition to opposing the induction of COX-2, iNOS, and MMPs and suppressing aggrecan synthesis by IL-1, activators of the peroxisome proliferator-activated receptor 7 (PPAR7), including the endogenous ligand 15-deoxy-A12'14 prostaglandin J2 (PGJ2), inhibit IL-1-induced expression of mPGES-1 [36,118]. COX-2 is also involved in the chondrocyte response to high shear stress, associated with reduced antioxidant capacity and increased apoptosis .
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