Retinoic acid is a potent regulator of growth plate chondrogenesis

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.