Interleukin 1β Suppresses Transforming Growth Factor-Induced Inorganic Pyrophosphate (PPi) Production and Expression of the PPi- Generating Enzyme PC-1 in Human Chondrocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 22; pp. 10364 - 10368
• Main Authors: Lotz, Martin, Rosen, Fred, McCabe, Greg, Quach, Jacqueline, Blanco, Francisco, Dudler, Jean, Solan, Joell, Goding, James, Seegmiller, J. Edwin, Terkeltaub, Robert
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 24.10.1995; National Acad Sciences
• Subjects: Adult; Aged; Alkaline Phosphatase - metabolism; Arthritis; Ascites; Blotting, Western; Cartilage; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cell culture techniques; Cells, Cultured; Chondrocytes; Culture Media, Conditioned; Diphosphates; Diphosphates - metabolism; DNA; DNA - metabolism; Gene Expression - drug effects; Homeostasis; Humans; Interleukin-1 - pharmacology; Kinetics; Membrane Glycoproteins - biosynthesis; Messenger RNA; Middle Aged; Phosphatases; Phosphoric Diester Hydrolases; Plasma cells; Pyrophosphatases - metabolism; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.22.10364

Articular cartilage chondrocytes have the unique ability to elaborate large amounts of extracellular pyrophosphate (PPi), and transforming growth factor β (TGFβ) appears singular among cartilage regulatory factors in stimulating PPiproduction. TGFβ caused a time and dose-dependent increase in intracellular and extracellular PPiin human articular chondrocyte cultures. TGFβ and interleukin 1β (IL-1β) antagonistically regulate certain chondrocyte functions. IL-1β profoundly inhibited basal and TGFβ-induced PPielaboration. To address mechanisms involved with the regulation of PPisynthesis by IL-1β and TGFβ, we analyzed the activity of the PPi-generating enzyme NTP pyrophosphohydrolase (NTPPPH) and the PPi-hydrolyzing enzyme alkaline phosphatase. Human chondrocyte NTPPPH activity was largely attributable to plasma cell membrane glycoprotein 1, PC-1. Furthermore, TGFβ induced comparable increases in the activity of extracellular 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 TGFβ-induced responses were completely blocked by IL-1β. Thus, IL-1β may be an important regulator of mineralization in chondrocytes by inhibiting TGFβ-induced PPiproduction and PC-1 expression.