Vitamin A deficiency and excess both cause abnormalities in mammalian longi
tudinal bone growth. Because all-trans retinoic acid (RA) is synthesized fr
om vitamin A, we hypothesized that RA regulates growth plate chondrogenesis
. Consistent with this hypothesis, a single oral dose of RA reduced the hei
ght of the rat proximal tibial growth plate. To determine whether RA acts d
irectly on growth plate, fetal rat metatarsal bones were cultured in the pr
esence of RA. In this system, RA inhibited longitudinal bone growth by thre
e mechanisms: 1) decreased chondrocyte proliferation, (assessed by H-3-thym
idine incorporation), particularly in the proliferative zone of the growth
plate; 2) decreased matrix synthesis (assessed by (SO4)-S-35 incorporation
into glycosaminoglycans); and 3) decreased cell hypertrophy (determined his
tologically). The growth-inhibiting effects of RA were completely reversed
by a retinoic acid receptor (RAR) antagonist. In the absence of exogenous R
A, this antagonist accelerated bone growth, as did an RA-specific neutraliz
ing antibody, suggesting that endogenous RA negatively regulates growth pla
te chondrogenesis. We conclude that RA, acting through RARs, negatively reg
ulates longitudinal bone growth by inhibiting growth plate chondrocyte prol
iferation, chondrocyte hypertrophy, and matrix synthesis.