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Retinoic Acid Is a Potent Regulator of Growth Plate Chondrogenesis

Developmental Endocrinology Branch (F.D.L., J.A.U., V.M., E.E.M., J.A.Y., K.M.B., J.B.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Department of Food Science and Human Nutrition (M.H.Z.), Michigan State University, East Lansing, Michigan 48824-1224

Address all correspondence and requests for reprints to: Francesco De Luca, Department of Pediatrics, University of Maryland School of Medicine, 22 South Greene Street, Room N5E13, Baltimore, Maryland 21201-1595. E-mail: fdeluca{at}peds.umaryland.edu

Vitamin A deficiency and excess both cause abnormalities in mammalian longitudinal bone growth. Because all-trans retinoic acid (RA) is synthesized from vitamin A, we hypothesized that RA regulates growth plate chondrogenesis. Consistent with this hypothesis, a single oral dose of RA reduced the height of the rat proximal tibial growth plate. To determine whether RA acts directly on growth plate, fetal rat metatarsal bones were cultured in the presence of RA. In this system, RA inhibited longitudinal bone growth by three mechanisms: 1) decreased chondrocyte proliferation, (assessed by ³H-thymidine incorporation), particularly in the proliferative zone of the growth plate; 2) decreased matrix synthesis (assessed by ³⁵SO₄ incorporation into glycosaminoglycans); and 3) decreased cell hypertrophy (determined histologically). The growth-inhibiting effects of RA were completely reversed by a retinoic acid receptor (RAR) antagonist. In the absence of exogenous RA, this antagonist accelerated bone growth, as did an RA-specific neutralizing antibody, suggesting that endogenous RA negatively regulates growth plate chondrogenesis. We conclude that RA, acting through RARs, negatively regulates longitudinal bone growth by inhibiting growth plate chondrocyte proliferation, chondrocyte hypertrophy, and matrix synthesis.

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