INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA INCREASE INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN-3 (IGFBP-3) PRODUCTION AND IGFBP-3 PROTEASE ACTIVITY IN HUMAN ARTICULAR CHONDROCYTES

IGF-I is the major anabolic factor for cartilage matrix production. Ch ondrocytes and cartilage treated with interleukin-1 alpha (IL-1 alpha) , and chondrocytes from several models of inflammatory joint disease, exhibit reduced responsiveness to IGF-I. Since the IGF-binding protein s (IGFBPs) modulate the effects of IGF-I, we examined the effect of IL -1 alpha and tumor necrosis factor-alpha (TNF-alpha) on IGFBP producti on by normal human articular chondrocytes in primary culture. Western ligand blots and immunoprecipitation of conditioned medium samples sho wed that articular chondrocytes produced IGFBPs-2, -3 and -4 and glyco sylated IGFBP-4. Both IL-1 alpha and TNF-alpha increased chondrocyte p roduction of IGFBP-3, but did not alter IGFBP-4 production. The activi ty of a neutral metalloprotease with the ability to cleave IGFBP-3 was also increased by IL-1 alpha. These data suggest that the cytokines I L-1 alpha and TNF-alpha may act to reduce IGF-I access to chondrocytes by increasing production of IGFBP-3. This may be a factor in the decr eased matrix production in the inflammatory arthritides.