Down regulation of interleukin 1beta production in human osteoarthritic synovial tissue and cartilage cultures by aminoguanidine

Abstract

Objective-To evaluate the eVect of aminoguanidine (AG) on de novo interleukin 1 (IL1 ), nitric oxide (NO), and interleukin 1 receptor antagonist (IL1ra) production by osteoarthritic human synovial tissue and articular cartilage cultures. Methods-Synovial tissue and cartilage, obtained during surgery from 29 patients undergoing total knee or hip replacement for osteoarthritis, were cut into small pieces and cultured in the presence or absence of lipopolysaccharide (LPS) and test materials. IL1 , IL1ra, and NO were determined in culture media. The inducible nitric oxide synthase inhibitor, AG, was added to cultures in various concentrations (0.3-3 mmol/l). Results-In synovial tissue cultures AG (0.3, 1, and 3 mmol/l) decreased LPS (1 µg/ml) stimulated IL1 and NO release in the media in a dose dependent manner (p<0.05 at 1 mmol/l and p<0.05 at 0.3 mmol/l, respectively). In articular cartilage cultures AG (0.3, 1, and 3 mmol/l) decreased LPS (1 µg/ml) stimulated IL1 and NO release in the media in a dose dependent manner (p<0.05 at 1 mmol/l and p<0.01 at 0.3 mmol/l, respectively). Hydrocortisone (5 µg/ml) also significantly decreased LPS stimulated IL1 release in media of synovial tissue and cartilage cultures and NO in media of synovial cultures. AG (0.3, 1, and 3 mmol/l) decreased LPS (1 µg/ml) stimulated IL1ra levels in media of synovial tissue cultures in a dose dependent manner (p<0.05 at 1 mmol/l) but increased LPS (1 µg/ml) stimulated IL1ra release in media of cartilage cultures (p<0.01 at 3 mmol/l). The NO donor, nitroprusside (10, 30, 100, and 300 µg/ml) stimulated IL1 release in media of synovial tissue cultures in a dose dependent manner (p<0.01 at 100 µg/ml). AG and nitroprusside at the concentrations used had no toxic eVect on human synovial cells. Conclusions-NO synthase inhibitors may modulate osteoarthritis and articular inflammatory processes not only by decreasing NO synthesis but also by their eVects on IL and IL1ra production. (Ann Rheum Dis 2001;60:391-394) Cytokines have important roles in cartilage destruction in osteoarthritis (OA).1 2 Among them, it appears that interleukin 1 (IL1) has a key role 3 and nitric oxide (NO) also plays a part.4 Both IL1 and NO contribute to cartilage degradation and inhibition of its synthesis. Because IL1 was shown to stimulate NO production in osteoarthritic synovium and cartilage, 7 8 it has been suggested that the deleterious eVects of IL1 on articular cartilage are mediated, at least in part, by NO.9 10 Therefore, inhibitors of NO synthesis are being investigated as possible anti-arthritic agents.11 Aminoguanidine (AG) is a relatively selective inducible nitric oxide synthase inhibitor.

Evaluation of the inflammatory response in experimentally induced synovitis in the horse: a comparison of recombinant equine interleukin 1 beta and lipopolysaccharide

“…It is unclear if the lower expression of IL-1b in reIL-1b treated synovium is due to a lack of or minimal endogenous IL-1b production at PIH 8 that follows reIL-1b injection. Previous in vitro studies have reported LPS-induced IL-1b production in human OA synovial tissue and cartilage 39,40 ; however measurements were of protein concentrations and not gene expression. Exogenous IL-1b is rapidly cleared from the joint and does not stimulate endogenous production of IL-1b 21 , possibly allowing for a more representative evaluation of mediator response to IL-1b.…”

Advanced glycation endproducts and osteoarthritis

“…It is the only AGE inhibitor that has been studied in tissue from individuals with OA. Aminoguanidine decreased lipopolysaccharide-stimulated interleukin-1-beta and nitric oxide release from cultures of human synovial tissue and articular cartilage, obtained during total hip or knee arthroplasty surgery from patients with OA [51]. Aminoguanidine treatment also prevents AGE crosslink formation [52].…”

The differential effects of IL-1 and TNF-? on proinflammatory cytokine and matrix metalloproteinase expression in human chondrosarcoma cells

“…sues, elevated levels of IL-1 have been found in synovial fluids from patients with OA, indicating it may be generated by cells resident in joint tissues [3,4,31]. Although mRNA's coding for the two IL-1 isoforms (IL-1a & IL-1b) were isolated from human chondrocytes [32], the relative abundance of IL-1a and IL-1b protein is less clear [33].…”

“…The expression of inducible MMPs (MMPs 1, 3,9,13) in cartilage is strongly stimulated by inflammatory cytokines, such as IL-1b and TNF-a. In RA, high levels of MMPs are found in synovial fluid, cartilage, and invasive synovial pannus [16][17][18].…”