INTERLEUKIN-1-BETA SUPPRESSES TRANSFORMING GROWTH FACTOR-INDUCED INORGANIC PYROPHOSPHATE (PPI) PRODUCTION AND EXPRESSION OF THE PPI-GENERATING ENZYME PC-1 IN HUMAN CHONDROCYTES

Articular cartilage chondrocytes have the unique ability to elaborate large amounts of extracellular pyrophosphate (PPi), and transforming g rowth factor beta (TGF beta) appears singular among cartilage regulato ry factors in stimulating PPi production. TGF beta caused a time and d ose-dependent increase in intracellular and extracellular PPi in human articular chondrocyte cultures. TGF beta and interleukin 1 beta (IL-1 beta) antagonistically regulate certain chondrocyte functions. IL-1 b eta profoundly inhibited basal and TGF beta-induced PPi elaboration. T o address mechanisms involved with the regulation of PPi synthesis by IL-1 beta and TGF beta, we analyzed the activity of the PPi-generating enzyme NTP pyrophosphohydrolase (NTPPPH) and the PPi-hydrolyzing enzy me alkaline phosphatase. Human chondrocyte NTPPPH activity was largely attributable to plasma cell membrane glycoprotein 1, PC-1. Furthermor e, TGF beta induced comparable increases in the activity of extracellu lar PPi, intracellular PPi and cellular NTPPPH and in the levels of PC -1 protein and mRNA in chondrocytes as well as a decrease in alkaline phosphatase. All of these TGF beta-induced responses were completely b locked by IL-1 beta. Thus, IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi prod uction and PC-1 expression.