Retinoic Acid is a Potent Regulator of Linear Growth • 413

Abstract

Both vitamin A deficiency and excess cause abnormalities of linear growth. Since vitamin A is a retinoid precursor, we hypothesized that retinoids act in the growth plate to regulate longitudinal bone growth. To test this hypothesis, we administered a single oral dose (300 mg/kg) of all-trans retinoic acid (RA) to 5-week old rats. RA decreased the height of the proximal tibial growth plate by 66% (vs. vehicle-treated rats, p<0.0001). To determine whether RA acts directly on the growth plate, whole fetal rat metatarsal bones were cultured for 2 days in the presence of RA (1μM). RA suppressed longitudinal bone growth (-3 ± 10 vs. 80 ± 8 μm/d, RA vs. control, mean ± SEM, p<0.0001). We next assessed each major component of longitudinal bone growth: proliferation, cellular hypertrophy, and cartilage matrix synthesis. RA suppressed cell proliferation to 54% of control (p<0.001, assessed by 3H-thymidine incorporation). Autoradiography demonstrated that cell replication was predominantly reduced in the proliferative zone chondrocytes of the growth plate. RA also suppressed matrix synthesis to 55% of control (p<0.001, assessed by35 SO4-incorporation into glycosaminoglycans) and suppressed chondrocyte hypertrophy to 5% of control (p<0.001, determined histologically).