Nitric oxide inhibition of IGF‐1 stimulated proteoglycan synthesis: Role of cGMP

Abstract

Insulin-like growth factor (IGF-1) is critical for normal development and maintenance of cartilage, however arthritic cartilage responds poorly to IGF-I; part of this insensitivity is mediated by nitric oxide (NO). These studies test if cGMP is responsible for NO dependent insensitivity to IGF-I in chondrocytes in situ in organ culture and in monolayer culture. Lapine cartilage and chondrocytes in monolayer culture and cartilage from osteoarthritic human knees were used. Tissues were exposed to NO from iNOS induced by IL-I, and proteoglycan synthesis in response to IGF-1 was evaluated in the presence and absence of cGMP dependent protein kinase (PKG) inhibitors. PKG activators inhibited IGF-I responses in cartilage but not chondrocytes in monolayer. IL-I stimulated cGMP synthesis in both monolayer and organ cultures. However, PKG inhibitors in cartilage slices but not in monolayer cultures restored response to IGF-1. PKG activity was detected in both fresh and monolayer chondrocytes, confirming this part of the cGMP signal cascade is intact in both of the preparations evaluated. Arthritic cartilage response to IGF-I was restored by both NG-monomethyl-L-arginine inhibition of NO synthesis and P K G inhibitors. The data suggests that cGMP mediated effects are critical to NO actions on chondrocytes in situ in the cartilage matrix and supports a role for cGMP in the pathophysiologic effects of NO in osteoarthritis.

Biomechanical signals and the C-type natriuretic peptide counteract catabolic activities induced by IL-1β in chondrocyte/agarose constructs

“…NO will change the function of other heme-containing proteins, such as COX-2 and increase PGE 2 production. In a previous study, overstimulation of the PKGI pathway was shown to block IGF-1-induced proteoglycan synthesis in chondrocyte monolayers [46]. Indeed, it was previously reported with human chondrocytes that enhanced cGMP levels lead to alterations in the PDE5 subtype and matrix breakdown.…”

Clinical and immunological characteristics associated with the presence of protozoa in sputum smears

“…Chondrocytes exposed to IL‐1, a cytokine that is elevated in arthritic synovial fluid, express iNOS and produce high levels of NO. Recent studies demonstrate that part of the IGF‐1 insensitivity observed in chondrocytes is caused by the induction of NO (17, 28, 29). Our initial experiments using iNOS‐knockout mice with ZIA confirmed that cartilage maintained the ability to respond to IGF‐1, although to a lesser extent (1) (Figure 1B).…”

Plasma Concentration of Insulin-like Growth Factor I (IGF-I) in Growing Ardenner Horses Suffering from Juvenile Digital Degenerative Osteoarthropathy

“…Moreover, IGF-I protects chondrocytes from apoptosis induced by a variety of stimuli, inhibits the catabolic effects of IL-I on proteoglycan synthesis in cartilage explants, and suppresses the degradation of cartilage matrix components by reducing matrix metalloproteinase-1 and metalloproteinase-8 expression and activity (Fosang et al, 1991;Hui et al, 2001;Oh and Chun, 2003;Lo and Kim, 2004,). However, nitric oxide generation could interfere with the anabolic effect of IGF-I (Studer et al, 2000(Studer et al, , 2003.…”