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).

To explore the role of endogenous RA signalling, we cultured metatarsals in the presence of AGN 193109 (1μM), an (RAR-specific) retinoid receptor antagonist. This antagonist accelerated bone growth (110 ± 10 vs. 60± 20 μm/d, antagonist vs. control, mean ± SEM, p<0.0001), suggesting that endogenous RA/RARs negatively regulate growth.

We conclude that retinoic acid negatively regulates linear growth by inhibiting all three components of growth plate chondrogenesis: chondrocyte proliferation, chondrocyte hypertrophy, and cartilage matrix synthesis. These findings raise the possibility that some growth disorders may be caused by abnormalities of retinoid function in the growth plate and that pharmacologic manipulation of the retinoid/RAR system may provide new therapeutic approaches to growth failure.