RETINOIC ACID STIMULATES PYROPHOSPHATE ELABORATION BY CARTILAGE AND CHONDROCYTES

Abnormal metabolism of extracellular inorganic pyrophosphate (PPi) by articular cartilage contributes to calcium pyrophosphate dihydrate (CP PD) crystal formation and the resultant arthritis known as CPPD deposi tion disease. The factors causing excess PPi elaboration in affected c artilage remain poorly defined. Retinoic acid (RA), a naturally occurr ing vitamin A metabolite, promotes cartilage degeneration and minerali zation, two correlates of CPPD crystal deposition. RA was examined as a potential modifier of cartilage PPi elaboration. All-trans RA (200-1 000 nM) increased PPi levels in culture medium of normal porcine carti lage and chondrocytes 2-3-fold over control values at 96 hours of incu bation (P < 0.01). IGF1 and anti-EGF antibody diminished the effects o f RA on PPi elaboration. RA modestly Increased activity of the PPi-gen erating ectoenzyme NTPPPH in culture medium (P < 0.01). As some RA eff ects are mediated through increased activity of TGF beta, a known PPi stimulant. we examined the effect of anti-TGF beta antibody on RA-indu ced PPi elaboration. PPi levels in medium were reduced from 30 +/- 7 m u M in cartilage cultures with 500 nM RA to 14 +/- 4 mu M PPi in carti lage cultures with RA and anti-TGF beta. Anti-TGF beta antibody. howev er, had no significant effect on RA-induced PPi elaboration in chondro cyte cultures. Thus, RA, along with TGF beta and ascorbate, can now be included in the list of known Pi stimulants. All three of these facto rs promote mineralization in growth plate cartilage; These data suppor t a central role for TGF beta in CPPD disease, and provide further evi dence linking processes of normal and pathologic calcification in cart ilage.