BONE MORPHOGENETIC PROTEIN-7 IN GROWTH-PLATE CHONDROCYTES - REGULATION BY RETINOIC ACID IS DEPENDENT ON THE STAGE OF CHONDROCYTE MATURATION

Although the bone morphogenetic proteins stimulate chondrogenesis, lit tle is known regarding their expression and regulation in growth-plate chondrocytes. The expression of bone morphogenetic protein-7 was exam ined in chick growth-plate chondrocyte cultures. Low basal levels of b one morphogenetic protein7 mRNA and protein expression were stimulated by increasing doses of all-trans retinoic acid, a metabolite of vitam in A. The addition of 10 mu M retinoic acid resulted in approximately a 6-fold increase in bone morphogenetic protein-7 mRNA levels. In cont rast, other growth regulators, including basic fibroblast growth facto r, transforming growth factor-beta, vitamin D, bone morphogenetic prot ein-6, bone morphogenetic protein-7, and parathyroid hormone-related p eptide, did not alter bone morphogenetic protein-7 transcript levels. The increase in bone morphogenetic protein-7 transcripts, although pre sent at 6 hours, was maximal following a 12-hour exposure to retinoic acid. Retinoic acid induction of bone morphogenetic protein-7 transcri pt levels was dependent on protein synthesis because the induction cou ld be blocked by cyclohexamide. In maturationally distinct subpopulati ons of chondrocytes separated by countercurrent centrifugal elutriatio n, retinoic acid markedly induced bone morphogenetic protein-7 mRNA le vels in the least differentiated chondrocytes but had no effect in the most terminally differentiated hypertrophic chondrocytes. Immunohisto chemical localization of bone morphogenetic protein-7 demonstrates its expression throughout the developing and adolescent growth plate cons istent with the constitutive pattern of expression seen in isolated ch ondrocytes. The addition of exogenous bone morphogenetic protein-7 to chondrocyte cultures stimulated maturation in undifferentiated chondro cyte populations. The data support a role for bone morphogenetic prote in-7 as an autocrine regulator of chondrocyte maturation in the growth plate. Regulation of bone morphogenetic protein-7 by retinoic acid ma y be important in normal growth and development as well as in patholog ic conditions of an excess or deficiency of vitamin A.