Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects

The aim of this study was to investigate the metabolic properties of human articular chondrocytes derived from young, aged and osteoarthritic subjects and their genetic adaptation to a catabolic challenge (i.e. the inflammatory cytokines interleukin-1alpha and tumor necrosis factor-alpha), in the absence or presence of diacerein, a drug potentially useful in osteoarthritis. Chondrocytes in primary culture were analyzed for newly secreted proteins, metalloproteinase synthesis and activity, and production of nitric oxide by-products. Results show that chondrocytes from normal but aged subjects present biochemical properties closer to osteoarthritic-derived cartilage than to normal young cartilage, as indicated by cell morphology, cell proliferation rate and pattern of protein secretion (in particular stromelysin-1 and interstitial collagenase). According to patient age and cartilage physiopathology, chondrocytes secrete increasing amounts of a protein identified by micro-sequencing as chitinase-like protein. Upon exposure to the inflammatory cytokines, chondrocytes, regardless the age or the status of the donor, significantly enhance their production of stromelysin-1, interstitial collagenase, interleukin-6 and interleukin-8. By contrast, the chitinase-like protein is not modulated by the cytokines. The pattern of protein secretion and metal loproteinase activity in chondrocytes from aged subjects appeared to be different from that of young patients, but was highly expressed in osteoarthritic chondrocytes. Diacerein, at therapeutically useful concentrations, consistently counteracts the stimulatory effect of cytokines on newly secreted proteins, metal loproteinase activity and nitric oxide production, whereas a selective nitric oxide blocker alone is ineffective. These data demonstrate that a specific gene program is turned on in cytokine-stimulated chondrocytes, which involves production of proteins engaged in remodeling and destruction of cartilage matrix. Part of these mechanisms appears to be operative also in unstimulated aged chondrocytes. Diacerein largely prevents the metabolic alterations caused by cytokine exposure in human chondrocytes, possibly through its ability to block early intracellular mediators after cytokine stimulation, such as oxygen radicals. (C) 2002 Elsevier Science B.V./International Society of Matrix Biology. Published by Elsevier Science B.V. All rights reserved.