EFFECTS OF FIBROBLAST GROWTH FACTOR-2 ON LONGITUDINAL BONE-GROWTH

In vivo, fibroblast growth factor-2 (FGF-2) inhibits longitudinal bone growth. Similarly, activating FGF receptor 3 mutations impair growth in achondroplasia and thanatophoric dysplasia. To investigate the unde rlying mechanisms, we chose a fetal rat metatarsal organ culture syste m that would maintain growth plate histological architecture. Addition of FGF-2 to the serum-free medium inhibited longitudinal growth. We n ext assessed each major component of longitudinal growth: proliferatio n, cellular hypertrophy, and cartilage matrix synthesis. Surprisingly, FGF-2 stimulated proliferation, as assessed by [H-3]thymidine incorpo ration. However, autoradiographic studies demonstrated that this incre ased proliferation occurred only in the perichondrium, whereas decreas ed labeling was seen in the proliferative and epiphyseal chondrocytes. FGF-2 also caused a marked decrease in the number of hypertrophic cho ndrocytes. To assess cartilage matrix synthesis, we measured (SO4)-S-3 5, incorporation into newly synthesized glycosaminoglycans. Low concen trations (10 ng/ml) of FGF-S stimulated cartilage matrix production, b ut high concentrations (1000 ng/ml) inhibited matrix production. We co nclude that FGF-2 inhibits longitudinal bane growth by three mechanism s: decreased growth plate chondrocyte proliferation, decreased cellula r hypertrophy, and, at high concentrations, decreased cartilage matrix production These effects may explain the impaired growth seen in pati ents with achondroplasia and related skeletal dysplasias.