ASCORBIC ACID-INDUCED CHONDROCYTE TERMINAL DIFFERENTIATION - THE ROLEOF THE EXTRACELLULAR-MATRIX AND 1,25-DIHYDROXYVITAMIN-D

Chondrocyte terminal differentiation is associated with cellular hyper trophy increased activity of plasma membrane alkaline phosphatase and the synthesis of collagen type X. The hypertrophic phenotype of cultur ed chondrocytes can be stimulated by ascorbic acid but the underlying mechanisms for this phenotypic change are unclear. As ascorbic acid is central to many hydroxylation reactions, the possibility was examined that its pro-differentiating effects are mediated by its effects on c ollagen and vitamin D metabolite formation, In vitro studies indicated that ascorbic acid-induced chondrocyte alkaline phosphatase activity was inhibited by the addition of both collagen and proteoglycan synthe sis inhibitors, The addition of arginine-glycine-aspartic acid (RGD)-c ontaining peptides also resulted in lower alkaline phosphatase activit y, Chicks supplemented with dietary ascorbic acid had higher concentra tions of both collagen and proteoglycans within their growth plates bu t the chondrocyte maturation rate was unaltered. No evidence was obtai ned to suggest that ascorbic acid-induced collagen production was medi ated by lipid peroxidation, In addition, supplementation with dietary ascorbic acid resulted in higher serum 1,25-dihydroxyvitamin D-3 conce ntrations and increased chondrocyte vitamin D receptor number, Ascorbi c acid-treated chondrocytes maintained in vitro also had increased vit amin D receptor numbers but chondrocyte receptor affinity for 1,25-dih ydroxyvitamin Da was unaltered, These results indicate that ascorbic a cid promotes both chondrocyte matrix production and 1,25-dihydroxyvita min D-3 synthesis, accompanied by upregulation of the vitamin D recept or, Thus, ascorbic acid may be causing amplification of the vitamin D receptor-dependent genomic response to 1,25-dihydroxyvitamin D, result ing in promotion of terminal differentiation. Strong evidence is provi ded to support the hypothesis that ascorbic acid-induced chondrocyte t erminal differentiation is mediated by interactions between integrins and RGD-containing cartilage matrix proteins.